Aging Matters Magazine 'BRAUN' by International Antiaging Systems (IAS)

V3 ISSUE 36 2020 US $10 / EU €8 / GB £7

The IAS private members club magazine

GETTING LEANER AND STRONGER In this issue: Peptides Xxxxxxxin sports & space xxxxx (an interview with Professor Vladimir Khavinson)

How to Xxxxxxx

boost your xxxxx testosterone naturally

Growth hormone Xxxxxxx releasing xxxxx peptides (by Richard Walker, MD)

Specialist sports Xxxxxxx supplements xxxxx (by Marios Kyriazis, MD)

Testimonials

Contents

AUBREY DE GREY Ph.D. “IAS has shown great vision and leadership as an organization focused mainly on the provision of contemporary medical interventions against aging, and in also supporting the SENS Foundation efforts to hasten the development of much more powerful future interventions.

NICHOLAS PERRICONE M.D. “IAS is an outstanding resource for the finest, most up-to-date news and information on healthy aging. They also offer products of the highest integrity and efficacy. In fact, IAS is the world’s greatest source, (often the only source) for the most cutting-edge and advanced nutrients to ensure optimum health span and maximum life span.”

THIERRY HERTOGHE M.D. “IAS have a history of making throughout the world crucial, but difficult to access medications available to patients. IAS is one of the pioneering societies in antiaging medicine that has helped this new medical speciality move forward.”

JONATHAN V. WRIGHT M.D. “Every adult has the right to take care of his or her own personal health as he or she chooses. In the 20th and 21st centuries this universal human right has been nearly obliterated by an ocean of nanny state regulations and deliberate suppression of information by bureaucracies, with hidden and not-so hidden agendas. International Antiaging Systems is a beacon of useful health care information and a literal island of freedom of health care product choice in our otherwise unfree health care world.” WALTER PIERPAOLI M.D. “I have known IAS for many years and they are a qualified group who provide for me, my family and my patients. Their skill and professional capacity has liberated me from all sorts of problems concerning the search for guaranteed and often rare supplements, or anything which is available but problematic to find. Their service goes far beyond duty and helps in many ways to maintain optimal health.” FRANK SHALLENBERGER M.D. "The tools that are available today to treat the aging process are truly amazing. Thanks to IAS the field of Anti-Aging medicine has expanded to the point that feeling and functioning 10-20 years younger is easily achievable. Their information and product services are regularly used by my patients."

Testimonials 02 -Professionals comment on IAS........................ Welcome 03 -To the end of 2020 edition................................ Forefront 04 -Recent stories in the news................................. Peptides in sports and space! 10 -An interview with Professor Khavinson .......... Natural agents for testosterone 16 -The development of TestoXLR8Pro™............. Growth Hormone Releasing Peptides 24 -Dr. Walker updates us on this subject............... Specialist sports supplements 34 -Dr. Kyriazis explores the field..........................

Product Spotlights...............................................

Antiaging-Systems.com 54 -Where to find what you need............................

Welcome As I wrote the top line in the index ‘welcome to the end of 2020’ I thought that many of us may wish that same sentiment! I imagine that many of us want the events of 2020 to be behind us. Naturally, CV19 has disrupted the whole world this year and we all trust that it will not linger into 2021. As a result of furloughed staff, various shortages, and disruption to airmail and travel etc., we had to limit 2020 to just two Aging Matters™ magazines*, and here is that second, now the end of year edition. We have picked a subject that a lot of people care about as a New Year begins, basically how to get fitter. Thus, this edition is dedicated to gaining muscle mass, losing fat, and improving overall body composition. We have not included exercise and diet since those should be at the base of the health pyramid; this information is about taking matters

further, onto agents that can help achieve good results faster. Many people ‘give up’ a mere 6 weeks into their fitness regime, so by seeing results sooner it can become an impetus to stay on a healthy exercise program. In this issue you will discover a fascinating interview with Professor Vladimir Khavinson from Russia, it is all about how peptide bioregulators have been used at the Olympics and even by Cosmonauts. We also have Dr. Marios Kyriazis informing us about cutting-edge/ specialist nutrition in the sports field, plus there is a detailed report on a natural supplement called TestoXLR8Pro™ and its ability to raise testosterone levels. Meanwhile, Dr. Richard Walker, (a recognised world expert on growth hormone/IGF1), tells us about the potency of certain peptides to raise GH levels. It is true to say that the key hormones in the production of muscle and reduction of fatty tissue are testosterone, GH and IGF1, although you will also learn about other angles within this issue. I suspect many of us have had a pretty-much sedentary year with the lockdowns and ‘stay at home’ messages broadcast from every media outlet. But now we can all look forward to 2021 by being leaner, fitter, and stronger in every way. *PS We hope to return to 4 issues in 2021 being released in March, June, September, and December. Phil Micans, MS, PharmB Editor, Aging Matters™ Magazine Ward Dean, M.D. Medical Director, IAS Group Declaration: The IAS Aging Matters™ magazine is intended for IAS private club members (and therefore is not intended for the public). It focuses on the latest international nutritional, hormonal and drug therapies to help combat the signs of aging. These signs include the physical, mental and internal changes consisting of the diseases and disorders such as cancer, arthritis and senile dementias etc. However, the focus is upon the prevention of such aging diseases and disorders for the ‘healthy-aging’ individual. Copyright 2020: All copyrights are acknowledged. Whilst every effort has been made to ensure accuracy, no responsibility can be accepted for illustrations, photographs, artwork or advertising materials while in transmission or with the publisher or their agents. Disclaimer: All educational information is offered strictly under IAS terms and conditions. This information does not replace the advice of your physician and restrictions may apply in some countries. The opinions expressed by the writers may not be those of IAS nor the magazine. Terms and conditions are subject to change without notice.

www.aging-matters.com 3

FOREFRONT

CAN YOU SEE RIGHT INTO YOUR DOG’S EYES? Can you see right into your dog’s eyes or do they appear cloudy? A cataract is a common reason for clouding of the eye, the dog will have difficulty seeing especially at night. Eye drops containing N-acetlycarnosine (NAC) can dissolve cataracts in a dog’s eyes and owners notice improved visual behaviour within a month of treatment. Many dog owners also use these eye drops as a preventative measure for dogs whose breed are susceptible to cataracts or dry eye syndrome. The cloudiness caused by cataracts normally starts in the black dot of the eye. There are four stages of a cataract, incipient, immature, mature and hyper mature. A hyper mature cataract has a risk of rupturing that can result in blindness, but early action could save your dog from having surgery. Is your dog too small or too old for cataract surgery? Eye drops containing N-acetlycarnosine can be a blessing for dogs that are too old or too small for cataract surgery. The eye drops are the most successful non-surgery treatment for dogs and other animals such as horses, cats and rabbits. Dry eyes and no tears… The drops can also help ‘dry eyes’ in animals, this is where the eyes don’t produce tears and they become painful. It is caused by a fault in the dog’s immune system where tear glands are attacked and destroyed. What dogs are most prone to cataract problems? Our four-legged friends seem almost human at times and like us, their eyes water, they get encrustations and infections. Those complaints should be looked at by a vet. 4

It’s no walk in the park when your dog has health problems so keep your eyes open and look for signs.

Breeds most prone to cataract problems are: • English Springer Spaniels • Siberian Huskies • Poodles • Collies • Boston Terriers • Great Danes

eyes, on closing the eyelid the drops spread across the surface of the eye.

• Squinting and scratching around the eyes

Putting eye drops in your dog’s eyes This can be a very stressful time for the dog and the owner, equally, a dog may get stressed when visiting a vet to have the eye drops put in. The simple fact is if your dog has eye problems it is a process that needs to be done that in the long term could prevent your dog from going blind.

• Excessive discharge sometimes green in colour

When applying eye drops, it’s a matter of finding what works for you and your dog, different experts have different suggestions. • Position the dog in the corner of the room and approach the dog face on with the drops • Stand behind the dog and position his butt next to your belly reaching over the dog to insert the drops • Straddle larger dogs to apply drops • Use a relaxed approach from the front with someone comforting the dog from behind

• German Shepherds

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Dogs and eye conditions There are obvious signs that your precious walking companion has eye problems. Keep your eye out for the following:

There are obvious signs that your precious walking companion has eye problems. Keep your eye out for the following:

• Redness and cloudiness • Sludge accumulating in the corner of the eye • A decrease in tear production • Unequal pupil size • Eyes sinking into the socket • Bumping into furniture • Not being able to find the water bowl • Lethargy • Loss of appetite

Our K9 best friends Dogs as pets know when we are sad and come to comfort us, they give their paw to please us and they become a big part of the family. Sadly, they aren’t immortal although we wish they were, they get ill just like we do so it’s our job as dog owners to give them the best chance of a long and healthy life. Providing for them and protecting them in a clean-living environment. Making sure that there is always fresh water available and feeding them a quality diet and preventing obesity. Giving plenty of opportunities to exercise and spending time with your dog to build your relationship. The dog lover’s good health apps Being a good dog owner involves keeping vaccinations up to date, making sure they have any medication they need for health issues and treatments for flea or tick control. This can be made easier by using relevant apps and here are four that have been recommended by Jim Dobies DVM veterinarian and president of Urgent Vet in Charlotte, North Carolina and Tampa, California. 5

FOREFRONT

1. Pet First Aid – an American Red Cross app for dog owners with illustrations and videos about dog emergencies such as falls, burns and seizures. 2. Animal Poison Control Center – a searchable database to determine whether something that has been consumed is cause for concern. 3. Fitbark – the app is connected to a fitness monitor which tracks your dog’s fitness and activity. 4. Vitusvet – it can access an entire medical history for your dog and give a reminder when your dog is due to have any medications. Having a dog in your life is a wonderful thing, they can bring so much joy. Keep your eye out for eye problems and with early diagnosis and good pet care you can enjoy the company of your four-legged friend for years.

FOREFRONT

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References 1. https://en.wikipedia.org/wiki/Cornea

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2. https://en.wikipedia.org/wiki/Corneal_neovascularization 3. https://en.wikipedia.org/wiki/Cataract 4. https://en.wikipedia.org/wiki/Glaucoma 5. https://en.wikipedia.org/wiki/Nuclear_sclerosis 6. https://en.wikipedia.org/wiki/Uveitis 7. https://pets.webmd.com/features/pet-apps 8. https://apps.apple.com/us/app/pet-first-aid/id780415389 9. https://apps.apple.com/us/app/animal-poison-by-aspca/id954896166 10. https://apps.apple.com/us/app/fitbark-dog-gps-health/id937936853 11. https://apps.apple.com/us/app/vitusvet-pet-medical-records/id955252538

A FIT BODY GOES WITH A FIT MIND

Disclaimer: All educational information is provided under the IAS terms and conditions which may change without notice. Restrictions may apply in some countries. (*plus S&H).

It’s time to change that lazy habit and get moving not only to improve your physical shape and well being but to actually change the structure of your brain and improve your cognitive function. Yet another great reason to exercise and hopefully, knowing that – is the motivation that you need to start raising your pulse rate. Remember, physical activity doesn’t have to involve trainers and pounding the streets, a bad back and weak knees shouldn’t stop you from some form of exercise. Studies have revealed that a fit body goes with a fit mind According to the experts, physical fitness can reduce the risk of dementia, Parkinson’s disease, schizophrenia, relieve depressive symptoms and so much more. Fitness is a preventable risk factor for brain health. Physical fitness improves cognitive function… Research has revealed that physical activity boosts cognitive performance. When exercising, white matter in the brain relays messages between different parts of the organ and improves brain health. So, get moving because studies have shown that inactivity can decrease cognitive performance. Are you struggling to concentrate when you sit for hours trying to work or been stuck on a crossword for days? Go for a walk, hit the gym, swim laps

– do anything that raises that pulse rate and your life could become so much clearer and healthier. White matter – the brain’s superhighway… White matter is the bulk of the deep parts of the brain. It consists of bundles of axons, long slender nerve cells and the whiteness comes from a waxy coating. The nerve cells pass messages to distant regions of the brain, the brain’s superhighway. White matter keeps developing into your 20’s but like many organs in the body, it can carry disease. White matter disease is progressive and can develop with age resulting in conditions such as Alzheimer’s or Multiple Sclerosis. Keep fit for a healthy brain The detailed study…Physical fitness improves cognitive function According to MedicalNewsToday, the largest most detailed study of its type concludes that there are links between fitness, white matter and improved cognitive performance. Improved mental powers are associated with white matter integrity. It was also found that physical activity boosts the cognitive performance of people of all ages and with cognitive impairments. The study discusses the different variables that play an important role in their findings such as blood pressure, body mass index, glucose levels etc. Scientists from the University Hospital Muenster in Germany took data from the 7

FOREFRONT

Human Connectome Project which included MRI brain scans from 1,206 adults with an average age of 28.8 yrs. 1,204 participants completed a walking test for two minutes and scientists assessed their memory, reasoning, sharpness, judgement and other parameters. The test revealed that those that performed better in the two-minute walking test performed better in all but one of the cognitive tests. The researchers lead by Dr Johnathan Repple were surprised to find that even in young people cognitive performance decreases as fitness levels drop. Dr Repple concluded that a basic level of fitness seems to be a preventable risk factor for brain health. How can you get more white matter?

Once you reach your 50’s you can’t create more white matter in your brain but you can delay it depleting rapidly by looking after your health by: • Performing 2.5hrs of exercise a week • Giving up smoking • Reducing alcohol consumption, even better – don’t drink alcohol at all • Avoiding high blood pressure • Eating a diet that is low in fat, sugar and salt • Sleeping well

Fit body, fit brain and motivation… With all that knowledge about fitness and the structure of the brain are you still struggling to find the motivation to exercise? Have you ever felt you were just going through the motions? Struggling to feel 8

engaged with seemingly mundane aspects of your fitness journey?

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“To keep the body in good health is a duty…otherwise, we shall not be able to keep the mind strong and clear.” – Buddha References and further reading… 1. Physical fitness linked to better brain function: https://www.medicalnewstoday. com/articles/326310.php 2. White matter: The brain’s flexible but underrated superhighway: https://www. medicalnewstoday.com/articles/318966.php 3. Visualization: Unlock the power of your mind: https://www. uncommonsensephysique.com/visualization-unlock-the-power-of-your-mind/

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PEPTIDE BIOREGULATORS IN SPORTS AND SPACE

PEPTIDE BIOREGULATORS IN SPORTS AND SPACE An interview with Professor Vladimir Khavinson PM: “Professor Khavinson, thank you very much for taking your valuable time today to talk about how peptide bioregulators are being utilized in sports and even in space.”

VK: “My pleasure Phil, after many decades of research, it is pleasing to see others taking an interest in our work.” PM: “We have talked about the peptide bioregulators before, and we have highlighted your research and your many published papers. But, just in case there are people reading this for the first time and are unaware of the background, do you think you could please sum up the importance of your findings in a few words?”

VK: “Certainly, to distil everything down to simplicity, after many years of intense studies, we found that short-chain peptides, these are aminoacids from 2 to 4 in length -that can be found in foodstuffs- act as gene switches and they can be used orally since they survive stomach degradation. They can activate, or silence specific genes very

accurately. Therefore, we gave them the name of peptide bioregulators as they can ‘perform’ in both directions. So, they can now be used as tools to improve hormonal and tissue reactions; they can be thought of as the epigenetic control in aging.” PM: “Which reminds me that we have worked on a scientific book together titled peptides in the epigenetic control of ageing.”

VK: “A very nice book Phil and you have also created another nice book for the public called the peptide bioregulator revolution.” PM: “Thank you for mentioning that. So, Professor Khavinson, what is the background of using peptide bioregulators in sports and athletics in Russia?”

VK: “The history is a very long one, it all started in 1980 when the Olympic team took our peptides. We had other sports people too, from soccer players, to tennis and track and field athletes.”

Professor Khavinson is the Director of the Saint Petersburg Institute of Bioregulation and Gerontology, Vice President of the Gerontological Society of the Russian Academy of Sciences, Head of Gerontology and Geriatrics at the Mechnikov State Medical University, Chief of the Department of the Pavlov Institute of Physiology. He is a specialist in gerontology and geriatrics and a Doctor of Medical Sciences and the former European Chair of the International Association of Gerontology and Geriatrics (2011-2015). The following interview was conducted with Professor Khavinson (VK) by Phil Micans (PM).

PM: “Why did they use them?”

VK: “Firstly, it was for rehabilitation, especially when taken before championships and major competitions and afterward they took them for restoration. It was for a restoration of health, and fundamentally it was a restoration of protein synthesis. This is of paramount importance to sports people.” PM: “How is this protein synthesis possible?”

VK: “The peptide bioregulators act on the genes that regulate protein synthesis. And protein synthesis promotes good function in a step-by-step process.” PM: “Have there been any side-effects with this process?”

VK: “Absolutely none, the peptide bioregulator quantity is relatively low, but they are also completely natural and found in our food. Typically, these peptide bioregulators are made up of 2, 3, 4 aminoacids and they act as keys for interaction and regulation for specific genes. So, for example, the heart peptide bioregulator will interact with only genes associated with the heart and so on.” PM: “I see, and what about sports people, what kinds of peptide bioregulators favor them?”

VK: “Quite a few actually, in our experience, it is heart, brain and cartilage. In fact, the best effects were from a combination of 6 peptide bioregulators, those being blood vessels, brain, thymus, cartilage, heart, and liver. This combination was recommended and used after a lot of scientific work.”

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PEPTIDE BIOREGULATORS IN SPORTS AND SPACE

effects can last some time. Of course, it depends on your age/ state of health, for example those in a bad condition need to be more regular in dosing than those in poor condition etc.”

PM: “Were there any other groups who were recommended this protocol?”

VK: “Yes, they were also used by Cosmonauts too and elite military forces, including submariners. We even helped people who were at the Chernobyl disaster with them. But I want to emphasize that the best results were always when the peptide bioregulators were used in combination. After all, health is not derived from one organ. Today, we can say that we have 40 years of both investigation and application.” PM: “Very interesting Professor Khavinson, may I ask if there was any use recorded in normal people, I mean civilians undertaking regular jobs?”

Professor Vladimir Khavinson with the gold winning members of the Russian Olympic team

VK: “As they were all workers, they were aged from 35 to 60 years old.” PM: “Did you try this kind of experiment again elsewhere?”

VK: “Yes, we had a long-term study of people working in factories. It was a large company called GAZPROM, responsible for the country’s gas supply. The participants worked in Siberia, which as you know has a harsh climate. We had 11,000 people in our study.”

VK: “Indeed, we worked at the time with the largest manufacture of vehicles in the Soviet Union, and here our results were 2.5 times less illness and morbidity in the peptide bioregulator treated group compared to the controls, it was a similar and confirming result.”

PM: “Professor Khavinson- did you just say there were eleven thousand people in your study?”

PM: “So you have shown that these peptide bioregulators benefit persons who work in extreme conditions and sports people too. Do you think that the new kinds of pressure jobs, such as those in corporate and banking etc., can benefit from the same technology?”

VK: “Yes.” PM: “That’s incredible! Please continue.”

VK: “3000 of the 11,000 were the control group, the remainder were divided into different groups using the blood vessel, thymus and pineal peptides, or combinations of them. We found that in the peptide bioregulator groups there was less ill health and morbidity compared to the control group, in fact it was 2.8 times less. It is a massive difference, to be nearly 3 times less likely to be ill.”

VK: “Absolutely, if you have chronic stress then taking a combination every month and perhaps repeating every 3 months, maybe even every 6 months can be very beneficial.”

PM: “How old were the individuals in this trial?”

VK: “That is correct Phil. We can switch on, or silence particular genes and those

PM: “So unlike, let us say vitamins, or even hormones, there’s no need to take the peptide bioregulators every single day.”

PM: “One particular peptide that stands out to me, that could interest a lot of sports people is the muscle peptide bioregulator. Could you say a few words about it please?”

VK: “The muscle peptide bioregulator interacts with genes that are responsible for the fiber development growth in muscles. It is a unique food supplement, as I have said before, all these peptide bioregulators can be found in food, these extracts are of course stronger and precise, but they all help to explain epigenetics.” PM: “Can the muscle peptide assist persons with sarcopenia?” [muscle wastage]

VK: “Yes, but it is better for that disorder to use a combination, that’s the muscle peptide, plus thymus, cartilage, pineal and perhaps also the blood vessels. It may sound like a lot but approaching a significant problem like sarcopenia needs a multifaceted approach for the best possible outcome.” PM: “And moving away from disorders themselves, what about that age-old issue of physical energy? Which peptide do you recommend?”

VK: “I think this one belongs to the adrenal peptide bioregulator. Helping to support the numerous hormones that the adrenal produces is vital. Adrenal fatigue is a common problem that many people experience, usually resulting in sleep naps during the day. If we think that adrenal hormones like DHEA are the most common in blood, then their loss, which occurs with age, is well worth supporting naturally with

the adrenal peptide bioregulator.” PM: “Now you said earlier Professor Khavinson, that these peptides don’t need to be taken every day, that’s quite different to a hormone replacement program, where they are likely to be taken every day. Also, on a hormone replacement program one needs to be careful to avoid receptor downregulation, so if it were undertaken without proper controls, i.e. blood tests, it can lead to a permanent need for a particular hormone. How do the peptide bioregulators differ in this regard?”

VK: “Very nice question Phil. Our 40-years of experience in many thousands of patients shows us that the safety of peptide bioregulators is second-to-none. As gene switches, either the gene is on, or it is off, there is no middle ground. We gave these peptides the name ‘bioregulators’- why? Because they regulate in both directions. For example, if a patient is hypothyroid then the thyroid peptide bioregulator will encourage the thyroid to produce more thyroid hormones, but if a patient is hyperthyroid, it will not do so. Peptide bioregulators cannot induce supralogical doses of hormones, which could be the case in an unmonitored hormone supplement program.” PM: “So I suppose, we have reached that point, to ask if you can please tell us how a sports person should dose with the peptide bioregulators?”

VK: “Athletes can use the bioregulators during training, this can be 2-capsules of each that has been chosen for them for 10-days every month. But a month before a competition they usually increase the dosing to 2-capsules every day. But many will stop 2 to 3 weeks or so before the event and then wait about 2 to 3 weeks after the competition to start again.” 13

PEPTIDE BIOREGULATORS IN SPORTS AND SPACE

PM: “I do recall one of your fascinating lectures about the Russian girls’ gymnastic team, these were the girls who won Gold at the 2012 London Olympics. I understand they were tested and had unbelievably short telomeres! How did that happen?”

VK: “We saw a normalization of their telomeres for their age. This was a significant improvement, because of course these girls are only 20-years of age.”

[Just a little background here for our readers, telomeres are the caps at the ends of chromosomes that hold the DNA strand together. Longer telomeres have been linked with longevity and generally better condition and activity. Today, telomere tests can determine a biological age referred to as ‘teloage.’ One expects telomeres to shorten with aging and in persons with health issues. One does not expect to find short telomeres in extremely fit 20-something year old’s!]

VK: “I do think so, mainly because we have recently released a new publication that shows the normalization of telomeres in middle-aged people with our peptides. Plus, we are working with Dr. Bill Lawrence from the USA and we hope to publish on his results of a three-year study in the middle of 2021.”

VK: “It is true that telomere length can vary from individual to individual, despite their age. Of course, we can consider that too much or too little of virtually anything can be damaging. There is an argument that athletes at this level are over-exercising, resulting in certain damages.

VK: “As stated before, a combination of our peptides is always better, but the pineal bioregulator peptide, that is Endoluten® or Epitalon® are fundamental in this regard.”

These damages may not play out for many years to come, accordingly there are evidence that athletes do not live as long as the society average. This is all related to excessive stress and extreme/ continuous exercise is an excessive stress. Thus, telomeres are a marker of stress and of aging. These 20-year old girls had telomeres as short as the average 40year old person. We were so surprised we repeated this investigation, but we had the same results.” PM: “Fascinating, what was the result after the use of the peptide bioregulators on their telomere length?”

PM: “That’s a great elongation. Do you think it is possible for older adults?”

PM: “Is there a peptide bioregulator that stands out in regard to telomere normalization?”

PM: “Professor Khavinson, I’ve said this before, but I thank you for this amazing research. I think it is now beginning to filter down in the west, (at least by those on the forefront of health), just how important this technology is and that its precision to target an individual’s weak spots, without interfering with other aspects of their biochemistry is truly remarkable. We here at IAS will continue to monitor it and report back on all the findings, and I am especially excited to report on Dr. Lawrence’s patients next year. Professor Khavinson, I know how much of a busy man you are, so I thank you very much for finding the time to talk to us.”

VK: “Thank you Phil.”

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Disclaimer: All educational information is provided under the IAS terms and conditions which may change without notice. Restrictions may apply in some countries.

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

BOOSTING TESTOSTERONE NATURALLY Maximizing testosterone levels is a prime objective of bodybuilders intent on increasing muscle mass and strength as well as other athletes seeking to gain a competitive edge and rise to the top of their game. And for good reason. Testosterone, the primary male sex hormone, has been shown to produce powerful anabolic (muscle building) and performanceenhancing effects. But it's not just athletes who can benefit from optimizing their hormone levels; so can antiaging enthusiasts − both men and women over 40 − who wish to prevent physical decline, improve muscle mass and bone density, avoid agerelated diseases, and enhance libido and general well-being. Although hormone replacement therapy is frequently the go-to approach for restoring hormones depleted by aging, like testosterone, research shows that it is possible to boost your body's own testosterone production using specific nutrients. TestoXLR8Pro™ is a combination product containing multiple targeted and clinically tested ingredients that raise testosterone levels and optimize its metabolism in the body through a variety of diverse but complementary mechanisms for an overall additive and powerful effect. Ed. Note: Since testosterone itself is a controlled substance in many countries utilizing natural approaches to improve levels is both safer and legal. Intro to Testosterone Testosterone is the primary androgen (male sex hormone) in men, though it is present in women at lower levels. Testosterone is 16

produced in mainly in the testes in men, and to a lesser extent in the ovaries in women and the adrenal glands in both genders. Besides its role in the development of secondary sex characteristics and sperm production in men, testosterone is important for both men and women for a variety of essential metabolic functions, including maintaining healthy bone and muscle mass, limiting fat accumulation, and enhancing libido, mood, and vitality.

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12 11 10 9 8 7 6 5 4 3 2 1 0

TESTOSTERONE

45 50 55 60 Chronological Age

OH Figure 1: The typical reduction of testosterone in men with advancing age.

H O

Figure: Structure of Testosterone

Testosterone Levels Fall with Age, Raising Disease Risk Factors and Lowering Physical Function Testosterone is the primary androgen (male sAging leads to significant declines in sex hormone production, including testosterone, (see figure 1). This has been linked to several negative consequences. A study on over 500 healthy men between 20 and 80 years old found that various forms of testosterone in the bloodstream (total testosterone, free testosterone, and bioavailable testosterone) decline continuously with age, starting in young

[Note: Most testosterone in the bloodstream is bound to one of two proteins, sex hormone binding globulin (SHBG) or albumin. (We'll see more on SHBG later.) A small percentage, known as ‘free’ testosterone, remains unbound in the bloodstream. Albumin-bound testosterone and free testosterone are the bioavailable forms (with the ability to act on target tissues); testosterone bound to SHBG is inactive. Total testosterone refers to the sum of free and bound testosterone.]

cognitive deficits, (11-12) and decreased sex drive. (11) Levels of testosterone in women also fall with age (along with the significant decline of estrogen that occurs with menopause), which predisposes women to some of the same health risks. In addition, low testosterone negatively impacts body composition and can lead to decreased muscle mass and sarcopenia (the more marked loss of muscle mass and strength associated with aging), (11,13-15) reduced bone mineral density and osteoporosis, (11,16) increased abdominal fat, (11,8-9) and reduced physical function (17) in both men and women.

Steadily declining testosterone levels in men raises many risk factors including atherosclerosis, (2-3) cardiovascular disease, (4-5) prostate cancer, (6-7) diabetes and insulin resistance, (8-9) depression, (10)

The good news is, restoring testosterone to more youthful levels ameliorates these negative effects, as we will see below. Since this issue of Aging Matters™ is devoted to sports and athletics, let us take a closer

adulthood, resulting in markedly lower levels in older men compared to young men. (1)

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

look at the beneficial effects of testosterone enhancement on body composition (especially muscle mass) and physical performance. Testosterone Replacement Results in Muscle Mass Gains and Improved Performance Several studies on adults over 60 years old show that testosterone replacement results in increased muscle mass and strength, reduced body fat, and enhanced exercise capacity. (13, 18-19) For example, in one of these studies, older men who used 1% testosterone gel for three years exhibited better stairclimbing power, improved chest and leg press performance, and greater lean body mass gains than men administered placebo. (18) These studies employed hormone repla cement therapy using prescription testosterone gel, oral tablets, or capsules in order to raise testosterone levels. However, for those who choose not to use prescription hormone replacement, you can stimulate your endogenous testosterone production safely and effectively and obtain the same positive improvements in muscle mass, strength, and fitness with the powerful synergy of nutrients in TestoXLR8Pro™. What sets this product apart from a slew of other testosterone-enhancers on the market is the science that backs up each nutrient, and the fact that most are present in clinically effective doses (i.e., doses used in clinical trials). Now let's examine the studies that support each individual ingredient. Shilajit, Fenugreek, and Stinging Nettle Shilajit is a substance, found primarily in the Himalayas, formed over hundreds of years from the gradual decomposition of plants. Used primarily in Ayurveda, the traditional Indian system of medicine, shilajit can treat many conditions, including male infertility, and studies over the past decade show that it boosts testosterone 18

levels. In a clinical trial on men between 45 and 55 years old, 250 mg shilajit taken twice a day (500 mg daily, the equivalent daily dose in TestoXLR8Pro™) for 90 days increased total and free testosterone as well as DHEA (dehydroepiandrosterone), (20) a steroid hormone precursor that is a core component in most anti-aging regimens. In another study on infertile men, 100 mg shilajit administered twice daily for 90 days not only raised blood testosterone levels, but significantly improved sperm count. (21)

Another Ayurvedic ingredient, fenugreek (Trigonella foenum-graecum), also known as Methi in India, is an annual herb in the pea family with a diverse array of active components and a long history of use in treating a broad spectrum of conditions. Fenugreek is thought inhibit two enzymes, aromatase and 5-alpha-reductase, (22) that lower testosterone by metabolizing it to estrogen (estradiol) and dihydrotestosterone (DHT), respectively. Elevated estrogen, like low testosterone, can lead to the development of breast tissue and increase the risk of heart attack, prostate cancer, and other conditions. DHT is highly potent, and increased levels are associated with benign prostatic hyperplasia (BPH), prostate cancer, and hair loss (since 5-alpha-reductase is also found in the scalp). By interfering with age-related increases in activity of aromatase and 5-alpha-reductase, fenugreek prevents conversion of testosterone to these

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

undesirable metabolites. This action is important to older men in whom the activity of these enzymes tends to increase. A metaanalysis (a statistical analysis of several similar studies) on four clinical trials found that fenugreek extract has a significant effect on testosterone levels. (23) In one trial on men 43 to 70 years old, 600 mg per day of fenugreek seed extract (slightly more than the 500 mg dose contained in TestoXLR8Pro™) for 12 weeks improved total and free testosterone levels as well as sexual function. (24) A similar study on women (20 to 49 years old) over eight weeks found similar results: 600 mg fenugreek seed extract per day also raised their free testosterone levels while improving libido and sexual function, (25) a positive ‘side effect’ for some people. And in a trial on men receiving 600 mg fenugreek seed extract per day during eight weeks of resistance training, the supplement was well tolerated and resulted in "significant anabolic [muscle synthesizing] and androgenic [male hormone-producing] activity as compared with the placebo." It also led to a marked improvement in body fat percent. (26) Stinging nettle (Urtica dioica) root is a well-researched phytotherapy, often used to treat BPH, which acts by multiple pathways, including inhibition of aromatase in prostate tissue. (27-28) The herb has been shown to increase testosterone levels (as well as sperm count and motility) in animals. (29) Vitamin D Research over the past several years has revealed the multiple and extensive health benefits of vitamin D, from promoting bone mineralization to supporting immune, cardiovascular, and cognitive health, to modulating sex hormone production and fertility. But the term "vitamin" D is somewhat of a misnomer, since technically, it is not a vitamin, but a prohormone

(hormone precursor). Interestingly, vitamin D has been shown to influence testosterone levels in men. (30-32) A study on over 4,000 men to examine various metabolic disease risk factors found that lower 25-hydroxyvitamin D levels were associated with lower total testosterone levels. (31) [Note: 25-hydroxyvitamin D is the most abundant vitamin D metabolite in the blood and used in blood testing as an indicator of vitamin D status in the body.] Other studies show that vitamin D deficiency can lead to declines in muscle strength and function, and reduced physical performance, (33-34) probably at least in part due to vitamin D 's influence on testosterone levels. Conversely, supplementing with Vitamin D can raise testosterone levels and improve performance. In a noteworthy trial on healthy overweight men who were initially vitamin D deficient and low in testosterone, supplementation with 83 ug (3332 IU) vitamin D daily for one year significantly raised their 25-hydroxyvitamin D as well as total and free testosterone levels. (30) Vitamin D supplementation may also reverse the negative effects of vitamin D deficiency on muscle strength and boost exercise capacity, as it did in older women with initial low baseline values. (19) In fact, one group of researchers proposes that maintaining 25-hydroxyvitamin D blood levels above the normal reference range could have a dramatic effect in raising testosterone levels, increasing muscle function and strength, and decreasing recovery time from training. (34) [Note: TestoXLR8Pro™ contains the recommended daily allowance (RDA) for vitamin D for adults up to age 70, 600 IU. Your total vitamin D intake depends on the amounts contained in any other supplements you consume, such as a multi-vitamin, a vitamin D supplement, etc., the foods you eat, and the amount of sunlight you are exposed to (vitamin D is also synthesized 19

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

in the skin in response to sunlight). The reference range for 25-hydroxyvitamin D is 20-100 ng/ml, with optimal blood levels in the approximate range of 50-80 ng/ml, which can only be determined by blood testing; it usually requires between 2000 and 5000 IU of ingested vitamin D to reach optimal levels. Do not consume high amounts of vitamin D (i.e., vitamin D intake that would result in 25-hydroxyvitamin D blood levels approaching or above 100 ng/ml, as suggested in this last study) without first consulting your health care professional, as high levels may be potentially toxic.]

Zinc and Boron Zinc is an essential mineral crucial to multiple aspects of cellular metabolism and physiology, including the activity of over 100 enzymes, as well as immune function, protein synthesis, wound healing, growth 20

and development, sexual function, and hormone modulation. Zinc is not stored in the body, so regular dietary intake is required. Studies have shown that low zinc levels are linked with low testosterone, sexual dysfunction, and infertility in men, (35-38) and that oral zinc supplementation raises testosterone levels. (35,38) In a study on men 55 to 73 years old who were marginally zinc deficient, 30 mg zinc taken as an oral supplement for six months resulted in a doubling of their blood testosterone levels. (38) [Note: TestoXLR8Pro™ contains 15 mg zinc (the RDA is 8 mg for women and 11 mg for men). Multivitamins typically contain 10 to 15 mg zinc, so if you take a multivitamin in addition to TestoXLR8Pro™, that will add up to approximately 25 to 30 mg zinc daily which is in the dose range of this last study. Check your multivitamin and other supplement labels carefully since the upper recommended limit for zinc is 40 mg per day.] Boron is a trace mineral important to many aspects of health, including bone mineralization, inflammation reduction, antioxidant status, and sex hormone production. Although studies have shown conflicting results, a few do indicate that boron supplementation influences sex hormone levels in both men and women. A study on healthy male volunteers taking 10 mg boron daily for one week found significant increases in the men's free testosterone levels accompanied by decreases in estradiol. (39) Researchers believe that boron may interfere with the chemical interactions between testosterone and SHBG (a protein that binds testosterone), essentially causing an "uncoupling" of the two, (40) which would explain the rise in free testosterone in the male volunteers. This unbinding action mediated by boron, which frees up biologically active testosterone, may be

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

beneficial to aging men with elevated levels of SHBG and low free and total testosterone. In postmenopausal women, 3 mg boron per day markedly raised levels of both estradiol and testosterone. (41) Additionally, boron supplementation has been shown to increase blood levels of 25-hydroxyvitamin D in animals and humans, (42) which may be another mechanism by which boron raises testosterone. TestoXLR8PRO™ contains a source of soluble boron known as calcium fructoborate, a natural fructose-boron complex found in fruits and vegetables; a daily serving of TestoXLR8PRO™ provides 5 mg of elemental boron, which is in the range used in these studies. TetraSOD® Finally, the last ingredient we will discuss is superoxide dismutase (SOD), an antioxidant enzyme present in relatively high concentrations in the testes, where most testosterone is produced in men. Oxidative damage to tissues that manufacture testosterone may cause the hormone's levels to decline with age; antioxidants such as SOD may help prevent this damage. SOD can also counter the increased oxidative stress associated with exercise. TestoXLR8Pro™ contains a concentrated source of SOD known as TetraSOD®, derived from a marine phytoplankton strain grown under patent-pending technology. A study on exercise capacity in young football players demonstrated that 25 mg TetraSOD® (the equivalent dose in TestoXLR8Pro™) taken daily for one month improved several blood markers of oxidative stress and enhanced athletic performance. (43) Putting it All Together We have covered a lot of territory. First, we examined the negative impact of aging on sex hormone production (lowered testosterone, in particular) which results in the development of a variety of age-related diseases as well as physical declines such as bone and muscle loss and reduced function

in both men and women. Next, we learned that, thankfully, there is something we can do about it. Research has demonstrated that restoring testosterone to more youthful levels can ameliorate and even reverse these negative consequences of aging, leading to gains in muscle mass and strength and improved physical performance in both sexes. Hormone replacement therapy is often the first-line approach to restore deficient hormones, but there's a safe, effective, and prescription-free alternative − the combination of targeted and clinically tested nutrients in TestoXLR8Pro™. Most ingredients in the formulation are in the dose ranges used in clinical studies and, as we just reviewed, each one individually has been shown to influence endogenous testosterone levels; combined they exert an overall potent and synergistic effect. Some nutrients directly stimulate testosterone manufacture, while others block age-related processes that can deplete the hormone, such as binding to SHBG or conversion by enzymes to estrogen and DHT. Together, these various mechanisms improve and "revitalize" your biochemistry, promoting higher levels of free and total testosterone in your bloodstream for noticeable gains in mass, strength, and performance, with additional benefits to overall health. TestoXLR8Pro™ should be taken at a dose of one capsule three times daily. For best results, use as part of a comprehensive program which includes a healthy diet with ample servings of protein coupled with an exercise program with strength/weight training at least three times a week. There are dozens of testosterone-enhancers to choose from, but TestoXLR8Pro™, with its unique combination of clinically proven and multi-acting ingredients, is a cutting-edge product that will support your performance goals and general health. 21

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

References 1. Leifke E, Gorenoi V, Wichers C, Von Zur Mühlen A, Von Büren E, Brabant G. Age-related changes of serum sex hormones, insulin-like growth factor-1 and sex-hormone binding globulin levels in men: cross-sectional data from a healthy male cohort. Clin Endocrinol (Oxf). 2000 Dec;53(6):689-95. 2. Hak AE, Witteman JC, de Jong FH, et al. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab. 2002 Aug;87(8):3632-9. 3. Jones RD, Nettleship JE, Kapoor D, Jones HT, Channer KS. Testosterone and atherosclerosis in aging men: purported association and clinical implications. Am J Cardiovasc Drugs. 2005 5(3):141-54. 4. Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart. 2010 Nov;96(22):1821-5. 5. Ohlsson C, Barrett-Connor E, Bhasin S, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. J Am Coll Cardiol. 2011 Oct 11;58(16):1674-81.

BOOSTING TESTOSTERONE NATURALLY WITH TESTOXLR8PRO™

25. Rao A, Steels E, Beccaria G, Inder WJ, Vitetta L. Influence of a Specialized Trigonella foenum-graecum Seed Extract (Libifem), on Testosterone, Estradiol and Sexual Function in Healthy Menstruating Women, a Randomized Placebo Controlled Study.Phytother Res. 2015 Aug;29(8):1123-30. 26. Wankhede S, Mohan V, Thakurdesai P. Beneficial effects of fenugreek glycoside supplementation in male subjects during resistance training: A randomized controlled pilot study. J Sport Health Sci. 2016 Jun;5(2):176-182. 27. [No authors listed] Urtica dioica; Urtica urens (nettle). Monograph. Altern Med Rev. 2007 Sep;12(3):280-4. 28. Moradi HR, Erfani Majd N, Esmaeilzadeh S, Fatemi Tabatabaei SR. The histological and histometrical effects of Urtica dioica extract on rat's prostate hyperplasia. Vet Res Forum. 2015 Winter;6(1):23-9. 29. Jalili C, Salahshoor MR, Naseri A. Protective effect of Urtica dioica L against nicotine-induced damage on sperm parameters, testosterone and testis tissue in mice. Iran J Reprod Med. 2014 Jun;12(6):401-8. 30. Pilz S, Frisch S, Koertke H, et al. Effect of vitamin D supplementation on testosterone levels in men. Horm Metab Res. 2011 Mar;43(3):223-5.

6. Morgentaler A, Rhoden EL. Prevalence of prostate cancer among hypogonadal men with prostate-specific antigen levels of 4.0 ng/mL or less. Urology. 2006 Dec;68(6):1263-7.

31. Chen C, Zhai H, Cheng J, et al. Causal Link Between Vitamin D and Total Testosterone in Men: A Mendelian Randomization Analysis. J Clin Endocrinol Metab. 2019 Aug 1;104(8):3148-3156.

7. Hoffman MA, DeWolf WC, Morgentaler A. Is low serum free testosterone a marker for high grade prostate cancer? J Urol. 2000 Mar;163(3):824-7.

32. Lerchbaum E(1), Obermayer-Pietsch B. Vitamin D and fertility: a systematic review. Eur J Endocrinol. 2012 May;166(5):765-78.

8. Chen RY, Wittert GA, Andrews GR. Relative androgen deficiency in relation to obesity and metabolic status in older men. Diabetes Obes Metab. 2006 Jul;8(4):429-35.

33. Książek A, Zagrodna A, Słowińska-Lisowska M. Vitamin D, Skeletal Muscle Function and Athletic Performance in Athletes-A Narrative Review. Nutrients. 2019 Aug 4;11(8):1800.

9. Abate N, Haffner SM, Garg A, Peshock RM, Grundy SM. Sex steroid hormones, upper body obesity, and insulin resistance. J Clin Endocrinol Metab. 2002 Oct;87(10):4522-7.

34. Dahlquist DT, Dieter BP, Koehle MS. Plausible ergogenic effects of vitamin D on athletic performance and recovery. J Int Soc Sports Nutr. 2015 Aug 19;12:33.

10. Almeida OP, Yeap BB, Hankey GJ, Jamrozik K, Flicker L. Low free testosterone concentration as a potentially treatable cause of depressive symptoms in older men. Arch Gen Psychiatry. 2008 Mar;65(3):283-9. 11. Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C. Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol Metab. 2004 Mar;89(3):1174-80. 12. Hogervorst E, Bandelow S, Combrinck M, Smith AD. Low free testosterone is an independent risk factor for Alzheimer’s disease. Exp Gerontol. 2004 NovDec;39(11-12):1633-9. 13. Wittert GA, Chapman IM, Haren MT, Mackintosh S, Coates P, Morley JE. Oral testosterone supplementation increases muscle and decreases fat mass in healthy elderly males with low-normal gonadal status. J Gerontol A Biol Sci Med Sci. 2003 Jul;58(7):618-25. 14. Yuki A, Otsuka R, Kozakai R, et al. Relationship between Low Free Testosterone Levels and Loss of Muscle Mass. Sci Rep. 2013 May 10;3:1818. 15. Yuki A, Ando F, Otsuka R, Shimokata H. Low free testosterone is associated with loss of appendicular muscle mass in Japanese community-dwelling women. Geriatr Gerontol Int. 2015 Mar;15(3):326-33. 16. Burnett-Bowie SA, McKay EA, Lee H, Leder BZ. Effects of aromatase inhibition on bone mineral density and bone turnover in older men with low testosterone levels. J Clin Endocrinol Metab. 2009 Dec;94(12):4785-92. 17. Chiang JM, Kaysen GA, Segal M, Chertow GM, Delgado C, Johansen KL. Low testosterone is associated with frailty, muscle wasting and physical dysfunction among men receiving hemodialysis: a longitudinal analysis. Nephrol Dial Transplant. 2019 May 1;34(5):802-810.

Disclaimer: All educational information is provided under the IAS terms and conditions which may change without notice. Restrictions may apply in some countries.

35. Vecchio M, Navaneethan SD, Johnson DW, et al. Interventions for treating sexual dysfunction in patients with chronic kidney disease. Cochrane Database Syst Rev. 2010 Dec 8;(12):CD007747. 36. Fallah A, Mohammad-Hasani A, Colagar AH. Zinc is an Essential Element for Male Fertility: A Review of Zn Roles in Men's Health, Germination, Sperm Quality, and Fertilization. J Reprod Infertil. 2018 Apr-Jun;19(2):69-81. 37. Khedun SM, Naicker T, Maharaj B. Zinc, hydrochlorothiazide and sexual dysfunction. Cent Afr J Med. 1995 Oct;41(10):312-5. 38. Prasad AS, Mantzoros CS, Beck FW, Hess JW, Brewer GJ. Zinc status and serum testosterone levels of healthy adults. Nutrition. 1996 May;12(5):344-8. 39. Naghii MR, Mofid M, Asgari AR, Hedayati M, Daneshpour MS. Comparative effects of daily and weekly boron supplementation on plasma steroid hormones and proinflammatory cytokines. J Trace Elem Med Biol. 2011 Jan;25(1):54-8. 40. Bello M, Guadarrama-García C, Velasco-Silveyra LM, Farfán-García ED, 41. Soriano-Ursúa MA. Several effects of boron are induced by uncoupling steroid hormones from their transporters in blood. Med Hypotheses. 2018 Sep;118:7883. 42. Nielsen FH, Hunt CD, Mullen LM, Hunt JR. Effect of dietary boron on mineral, estrogen, and testosterone metabolism in postmenopausal women. FASEB J. 1987 Nov;1(5):394-7. 43. Pizzorno L. Nothing Boring About Boron. Integr Med (Encinitas). 2015 Aug;14(4):35-48. 44. Fitoplancton Marino, S.L. [Manufacturer of TetraSOD®] Effects of TetraSOD® as food supplement for peak physical performance.

18. Storer TW, Basaria S, Traustadottir T, et al. Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men. J Clin Endocrinol Metab. 2017 Feb 1;102(2):583-593. 19. De Spiegeleer A, Beckwée D, Bautmans I, Petrovic M; Sarcopenia Guidelines Development group of the Belgian Society of Gerontology and Geriatrics (BSGG). Pharmacological Interventions to Improve Muscle Mass, Muscle Strength and Physical Performance in Older People: An Umbrella Review of Systematic Reviews and Meta-analyses. Drugs Aging. 2018 Aug;35(8):719-734. 20. Pandit S, Biswas S, Jana U, De RK, Mukhopadhyay SC, Biswas TK. Clinical evaluation of purified Shilajit on testosterone levels in healthy volunteers. Andrologia. 2016 Jun;48(5):570-5. 21. Biswas TK, Pandit S, Mondal S, et al. Clinical evaluation of spermatogenic activity of processed Shilajit in oligospermia. Andrologia. 2010 Feb;42(1):48-56. 22. Nguyen SM, Ko Ko N, Sattar AS, Gucuk Ipek E, Ali S. Pulmonary Embolism Secondary to Testosterone-Enhancing Herbal Supplement Use. Cureus. 2017 Aug 6;9(8):e1545. 23. Mansoori A, Hosseini S, Zilaee M, Hormoznejad R, Fathi M. Effect of fenugreek extract supplement on testosterone levels in male: A meta-analysis of clinical trials. Phytother Res. 2020 Feb 11. 24. Rao A, Steels E, Inder WJ, Abraham S, Vitetta L. Testofen, a specialised Trigonella foenum-graecum seed extract reduces age-related symptoms of androgen decrease, increases testosterone levels and improves sexual function in healthy aging males in a double-blind randomised clinical study. Aging Male. 2016 Jun;19(2):134-42.

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GROWTH HORMONE RELEASING PEPTIDES

GROWTH HORMONE RELEASING PEPTIDES By Richard Walker, M.D. The origin of a novel GH secretagogue Bowers and Momany synthesized the first growth hormone releasing peptide using a novel approach to determine the then unknown sequence of a growth hormone releasing hormone (GHRH)1. They modified the structure of small opioid neuropeptides that possessed very weak GH-releasing activity, assuming that structural alteration might produce new peptides with greater efficacy. In fact, GHRP-6 was the first synthetic peptide of the series that elicited dose-related GH release in-vitro and invivo2. Additional modifications were produced to improve the original discovery, of which

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four emerged as most logical candidates for drug development, including GHRP-6 (HisD-Trp-Ala-Trp-D-Phe-Lys-NH2), Hexarelin (His-D-Mrp-Ala-Trp-D-Phe- Lys-NH2), GHRP-2 (D-Ala-D-β-Nal-Ala-Trp-D-PheLys) or pralmorelin which was most potent, and ipamorelin (Aib-His- D-2-Nal-D-PheLys-NH2) which persisted in the circulation longer than the other GHRPs3. Initially, observations of GHRP’s effects were confusing and resulted in their being differentiated from GHRH as a special group called growth hormone secretagogues (GHS) since GH was the first hormone whose secretion was known to be stimulated by them. Although GHS released

Dr. Walker is the founder of the Scientific Aging Research Academy (SARA) and is one of the serious academic scientists who for many years has supported antiaging research and is an expert in hGH replacement therapy. hGH (human growth hormone) has had a lot of interest in it, even since Dr. Daniel Rudman’s research in the 1980s, whereby he administered injectable GH to elderly individuals and after a 2 to 3 month period stated that many of their biological age markers had been reversed by 20-years! This included less fat tissue, more muscle mass, better skin elasticity and hair condition and a feeling of well-being. As you may imagine, such a result caused a furor, and Dr. Ronald Klatz produced a good book on the subject called; ‘grow young with HGH.’

Since Dr. Rudman’s publication, a lot more research has been undertaken and doses have been reduced somewhat. The recent published research of Dr. Greg Fahy has shown patients supplementing with hGH are able to rejuvenate their thymus gland. This has significant implications for improved immunity and is yet another benefit for this multi-factorial hormone when it is used correctly. Alas, many countries have decided that GH itself has anabolic properties and therefore must be a controlled substance. Since it is a 191-chain of aminoacids it can only be effective if it is injected. Therefore, many people have been looking for alternatives, both from a legal perspective and from a convenience perspective (i.e. no need to inject). The most promising of these at present are the GHRPs (growth hormone releasing peptides). As Dr. Walker has a lot of experience and knowledge from studying the role of GHRPs and their benefits for aging individuals, we asked him if he would kindly detail the technology and clinical facts behind their use. This article is his detailed reply.

GH, they did not behave as expected had the new molecules truly been GHRH or analogs of it such as sermorelin. Unlike GHRH, GHS was only weakly effective in vitro when incubated with pituitary tissue. To be effective, it required hypothalamic tissue to be present in the incubate. Paradoxically, when administered to healthy lab animals and later to humans it was more active than exogenous GHRH. This potency was lost when GHS was given to lab animals with hypophyseal stalk section or to human subjects suffering hypothalamic pituitary disconnection as the result of disease or trauma4. This led to speculation that GHS was releasing a heretofore unknown factor (‘U’ factor) from the brain5. The idea was reinforced by the observation that when GHRP was administered concomitantly with GHRH, its effect to elevate circulating GH was not simply additive to the anticipated responses of GHRH or that of its truncated analog, sermorelin. Instead it potentiated them, suggesting that the putative ‘U’ factor

complemented the GH-releasing effects of GHRH and GHS. Lesser potentiation was observed in vitro when GHS/GHRH were coincubated further suggesting that another factor(s) contributed to the potentiation of GHRH by GHS in-vivo. However, it is now known that full potentiation of GHRH in-vivo is due to GHS suppression of somatostatin as well as to stimulation of GHRH releasing neurons in the arcuate nucleus6. Discovery of ghrelin – Functional differences between GHRH/ Sermorelin and Ghrelin/GHRP GHS enhances GH secretion by different mechanisms and acts through different receptors from those for GHRH, somatostatin or opioid peptides. In 1996, Howard et al. cloned the GHS receptor (GHS-R), which was mainly found in the anterior pituitary and in the hypothalamus, and in other areas of the central nervous system7. While GHS downregulated these receptors, it was incapable of downregulating GHRH receptors in the same tissues. These different receptors

hypothalamus

GHRH

Ghrelin/GHS

SRIF

GHRH-R

GHS-R

SRIF-R

PKA

PKC Ca++

cAMP

somatotroph

GH release Figure 1: The representative model of interrelationships within the GH neuroendocrine axis8. 25

GROWTH HORMONE RELEASING PEPTIDES

Table 1. Elemental composition of GHRPs and their metabolites. POSITION AT GENERAL SEQUENCE

Modulation of cell proliferation and survival

Influence on food intake, sleep and behaviour

Influence on cardiac performances and vascular resistances

Stimulation of GH, PRL, ACTH and AVP secretion; Inhibition of gonadotropin secretion

GHRP2

Influence on energy metabolism

Influence on glucose metabolism

Influence on gastric acid secretion and mobility

Figure 2: The extra-pituitary effects of GHRP2 a potent ghrelin analog. As a functional analog of ghrelin, GHRP2 possesses similar effects of the native peptide (10).

and prolactin. Through these additional endocrine affects, the synthetic GHS peptides also markedly increase appetite and weight gain, modulate cell proliferation and survival, are cardioprotective, affect heart performance and vascular resistance, are immuno-supportive and anti-arthritic, influence gastric acid secretion and motility, energy/glucose metabolism, as well as exocrine and endocrine pancreatic function.

The endogenous ligand for these GHS receptors was discovered in the stomach and hypothalamus by Kojima et al (1999), thereby establishing a new brain-gut peptide family. Ghrelin, the name chosen for the new hormone was derived from ghre, the Indo-European root of the word grow 9.

These properties increase the potential of GHS for extra-GH management of diverse, maladaptive, age-related changes ranging from accumulation of reactive oxygen species (ROS) to cardioprotection (Figure 2).

A distinctive quality of GHS/ghrelin differentiating it from GHRH/sermorelin is that depending upon the dose administered, it releases pituitary peptides other than GH, primarily ACTH/adrenocorticoids

TRIVIAL

CODE

NAME

4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

GHRP-1 (3-7) GHRP-1 (3-7) FA GHRP-1 (3-6) FA GHRP-2 GHRP-4 GHRP-4 FA GHRP-5 GHRP-6 HEXARELIN HEXARELIN FA HEXARELIN (2-6) ALEXAMORELIN IPAMORELIN IPAMORELIN FA IPAMORELIN (1-4) FA

C-terminal form

aa-

Ala-

Trp-

(D-Phe)-

Lys-

NH2/OH

D-AiaTyrHisHisHisHisHisHisHis-

(D-β-Nal)(D-β-Nal)(D-β-Nal)(D-β-Nal)(D-Trp)(D-Trp)(D-Trp)(D-Trp)(D-Mrp)(D-Mrp)(D-Mrp)(D-Mrp)(D-2-Nal)(D-2-Nal)(D-2-Nal)-

AlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAlaAla-

TrpTrpTrpTrpTrpTrpTrpTrpTrpTrpTrpTrp-

(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)(D-Phe)-

LysLysLysLysLysLysLysLysLysLys-

NH2 OH OH NH2 NH2 OH NH2 NH2 NH2 OH NH2 NH2 NH2 OH OH

AlaAibAibAib-

Table 1: The structure-activity relationships for peptidergic GHS. (11)

Influence of exocrine and endocrine pancreatic function

initiated different metabolic cascades involving separate second messengers and ion fluxes (Figure 1).

COMPOUND

Structural characteristics favoring oral bioavailability Characteristic of the entire series of GHRPs, and necessary for their efficacy is the presence of alanine (Ala), tryptophan (Trp) and d-phenylalanine (D-Phe) within their central structure except for ipamorelin, the last in the series which lacks Ala and Trp, but retains D-Phe (Table 1).

tri-peptide moiety is a functionally significant attribute of all GHS peptides because they protect the molecules from endopeptidase attack and thus, make them orally bioavailable12. As shown in Figure 3, endopeptidases cleave peptides internally and thus, would have the potential to destroy the active moiety in GHS were it not protected by the d-amino acid isomers.

The presence of d-amino acids blocking each side of the internal, activity essential,

As a result of their oral bioavailability, GHRP2 and other GHS are now available

endopeptidase exopeptidase

exopeptidase

Met - Ala - Glu - Phe- Tyr - Lys - Phe - Leu

Table 1. Elemental composition of GHRPs and their metabolites. POSITION AT GENERAL SEQUENCE COMPOUND

TRIVIAL

CODE 1 2 3 26

C-terminal form

NAME

aa-

Ala-

Trp-

(D-Phe)-

Lys-

NH2/OH

GHRP-1 GHRP-1 (2-7) GHRP-1 (2-7) FA

Ala-

HisHisHis-

(D-β-Nal)(D-β-Nal)(D-β-Nal)-

AlaAlaAla-

TrpTrpTrp-

(D-Phe)(D-Phe)(D-Phe)-

LysLysLys-

NH2 NH2 OH

aminopeptidase

carboxypeptidase

Figure 3: Endopeptidases cleave peptides lacking internal d-isomers thereby promoting digestion and preventing oral bioavailability. 27

GROWTH HORMONE RELEASING PEPTIDES

as sublingual tablets that are a more convenient dosage form for daily use at home and especially during travel. A popular commercial brand of this dosage form is GHRP2Pro™ that is now available from IAS online. A popular commercial brand of this dosage form is GHRP2Pro™ that is now available from IAS online. Drug Development Despite the multiple benefits of GHS and the fact that they are safe, (no serious general pharmaco-pathological effects at dose levels showing GH-releasing activity have ever been reported), extensive basic research by university and other public sector scientists undoubtedly thwarted commercial development due to loss of patent protection and other competitive factors. However, some drug development was attempted, albeit unsuccessfully. For example, commercial development of GHRP-6 as a feed additive to improve milk production in cows was attempted by SmithKline Beecham during the midto late 1980’s but was never approved for use. Since GHS is orally bioavailable, the logic for this application was that it could be added in relatively large amounts to feed for dairy cattle. Directly relevant to the marketing attempt was the secondary effect of the peptides to stimulate prolactin release and thereby, potentially increase milk production. GHRP-2 (pralmorelin) was also under investigation for the treatment of growth hormone deficiency (GHD) and short stature (pituitary dwarfism), and was advanced to phase II clinical trials for these indications, but ultimately, was never marketed for them13. There have been few other specific drug development efforts to exploit clinical applications for GHS except as a diagnostic. 28

GROWTH HORMONE RELEASING PEPTIDES

Kaken-Japan, developed and received approval of GHRP-2 as a minor market product, i.e., a single dose formulation for assessment of adult GH deficiency14. This diagnostic application is the only currently regulated drug indication being marketed. Quantitative benefits of GHRP2 in aging Lacking extensive development of GHRP2 as a ‘big Pharma’ drug product, it became available for ‘off label’ application in antiaging medicine. Logically, the medical basis for such applications derived from the positive effects of recombinant human growth hormone (rhGH) on phenotype, e.g., increasing lean body mass, decreasing abdominal adiposity, improving skin tone, etc. as first reported by Rudman15. However, legal restrictions preventing its use for anti-aging purposes led to a search for other effective and safe means of GH replacement therapy (GHRT). Any GH stimulating component of the GH neuroendocrine axis can be used for GHRT with some degree of benefit. However, these are also potentially detrimental even though they bring some level of somatic rejuvenation. Unfortunately, hormones that act directly within the GH neuroendocrine axis can also degrade functional/ physiological interactive relationships thereby exacerbating age-like, maladaptive changes. For example, somatomedin (IGF-1 et al.) exerts negative and positive, long-loop feedback on GHRH and SRIF, respectively. Similarly, though negative, and positive feedback, rhGH essentially shuts down its own endogenous synthesis while stimulating SRIF release, depending upon the dose administered. To attempt to circumvent this problem, sermorelin, a truncated analog of GHRH

has been used to avoid negative feedback effects of rhGH and/or IGF-1 that can diminish production of intrinsic hGH by the adenohypophysis. However, ultra-short negative feedback involves GHRH/sermorelin upon its own endogenous production and positive feedback on SRIF producing neurons. Thus, these approaches limit their efficacy which wanes after extended use, indicating that use of specific hormones within the GH neuroendocrine axis for somatic benefits of GHRT should be weighed against their dysfunctional, physiological/neuroendocrine potential. In contrast to the specific effects of GHRT by peptides directly within the GH neuroendocrine axis, GHS enhances secretory performance because it mitigates the progressive, maladaptive dominance of intrinsic factors such as sermorelin/GHRH and somatostatin (Figure 4). As seen in Figure 4, GH release in response to GHRP2 was comparable in adolescents and middle-aged, adult subjects. In contrast, the response to GHRH was only modestly reduced in adolescents when compared with that of GHRP2. However, it was dramatically attenuated in the adult subjects. Thus, the data suggest that the synergistic response to GHRP2 in-vivo, is not dose related to endogenous GHRH, but rather just requires the presence of some quantum of the natural hormone to realize a significant part of its full stimulatory potential. The response to GHRP2 in adults also suggests that rapid recrudescence of GHRH neuronal elements may be evoked by the ghrelin analog. In contrast, the minimally additive effect of exogenous GHRH with endogenous GHRH in the adult subjects reflects an age-related decline in the latter neuropeptide and of increased somatostatin tone with advancing age17.

In the long term, by stimulating GHRH neurons, GHS sustains its receptors by direct effect and also due to association with dopamine receptors to form GHSR1a:DRD2 heteromers18. It also inhibits SRIF neurons, prevents desensitization of the GHRH receptor (GHRH-R)19-21 and reduction of GHRH-R messenger RNA accumulation22. Pituitary recrudescence is also facilitated by GHS because it recruits separate somatotrophs from its three subpopulations23. Through these effects, GHRP2 enhances efficacy of endogenous GHRH through synergy and promotes ‘feed forward’ that overrides negative feedback factors upon GHRH neurons. Since GHS enhances ‘feed forward’ by activating GHRH neurons essentially from outside the main axis, it shifts activity relationships thereby tending to support expression of GH secretory pulses which are a dominant characteristic of youthful animals and humans. Qualitative benefits of GHRP2 in aging Neuroendocrine aging represents a gradual process during which patterns of GH secretion that are modulated in 29

GROWTH HORMONE RELEASING PEPTIDES

young, healthy people, degrade slowly over time. During youth, normal GH secretion is expressed as minimal, basal serum concentrations upon which occur highly regulated pulses of the hormone. These pulsatile as well as nychthemeral secretory patterns are pre-eminent physiological features of healthy GH release and are critical to physiological regulation and long-term activation of the GH neuroendocrine axis.

STAT5b is a protein coding gene that affects sensitivity to GH.

Such pulsatile signaling resulting from intermittent release of GHRH from neurosecretory hypothalamic neurons consistent with prior and concurrent hypothalamic somatostatin tone preserves biosynthesis and secretion of somatotropin.

As previously shown, the potential quantitative benefits of GHRP2 derive from its robust ability to stimulate large amounts of GH from the pituitary. And its physiological/qualitative benefit results from its ability to restore spontaneous GHRH neuronal activity bursts that enhance feedback control dynamics and maintain pulsatile release of hGH from the pituitary gland.

Pulsatile GH signals also activate organspeciﬁc second messenger signaling pathways, such as the Signal Transducer and Activator of Transcription 5B (stat5B) in the liver, with subsequent induction of speciﬁc genomic responses in relevant target tissues.

Serum Growth homone (ug/L)

These are not equivalently induced by constant or disorganized GH stimuli. Thus, for anti-aging purposes, restoration of frequent, regularly occurring GH pulses is a very important physiological effect because it represents recrudescence of spontaneous GHRH neuronal activity bursts, enhancing the quality of feedback control dynamics.

As shown in Figure 5, restoration of GH pulses in older men and women was

The latter effects are demonstrated by relatively greater increase in IGF-1 after 30-d stimulation with GHRP-2. Presumably, similar effects can be achieved by anti-aging physicians using commercially available GHRP2Pro™. Age-changes in GH secretory dynamics at later stages of life are clinically measurable as frank alterations of the earlier patterns that can be quantified by measurement of pulse timing and amplitude. However, the subtle slowly varying features of such pulsatile change during the onset and early stages of senescence cannot be easily delineated quantitatively by such measurement. Thus, decay of earlier, organizational aspects of GH release can be quantified using the statistic, approximate

entropy (ApEn)25 which quantifies the persistence of (sub)pattern features in repetitive measurements over time 26,27. Notably, as applied to endocrine time-series, ApEn will detect alterations in underlying episodic behavior that are not reﬂected in peak occurrences or amplitudes, a point germane to many applications. In fact, ApEn statistical applications have unmasked consistent and signiﬁcantly greater secretory disorderliness with advancing age for the GH axis providing a direct barometer for the strength of the feedback system28. Such data would be important for predicting the state of neuroendocrine aging and theoretically as interventions become available, be valuable in knowing when to begin therapy. Since GHRP2 enhances ‘feed forward’ by activating GHRH neurons from outside the main axis, and thereby opposes age-associated degradation of regulatory control within the GH neuroendocrine axis, it is a logical consideration for GHRT by practitioners of anti-aging medicine.

Normal Males - Adults vs. Adolescent Children Adult Male Adolescent Male

GHRP2/GHRH ratio 20.5 1.5

24 12 0

Placebo

24 12 0

GHRH (1 μg/kg)

24 12 0

GHRP-2 (1 μg/kg)

40 30 20

IGF-I 101/131 24 12 0

To come

Placebo

IGF-I 887/112

118/136 24 12 0

GHRH (1 μg/kg)

85/101

100/184 24 12 0

GHRP-2 (1 μg/kg)

79/138

GHRP-2

330

300

270

255

240

225

210

120

-15

-30

GHRH Time (Minutes)

Figure 4: Comparative responses to IV administration of GHRH or GHRP in adolescent and adult subjects. Single SC injections of GHRH and GHRP2 were administered separately three hours apart (16). 30

accomplished clinically using GHRP-2 but not comparable doses of GHRH or its truncated analog, sermorelin. These responses represent restoration of feedback relationships and increased coupling with interdependent neuroendocrine components.

Figure 5: Comparative stimulation of pulsatile GH release and IGF-1 concentrations by GHRH vs GHRP-2 in healthy older men and women after 30 days of treatment. Italicized numbers in the top right of each dose response are IGF-1 concentrations at the beginning and end of each treatment period.24

GROWTH HORMONE RELEASING PEPTIDES

Conclusion Because of its feed-forward effects and oral bioavailability, GHRP2 hormone replacement may provide a more holistic approach to GH-directed therapy. Compared with others, its more effective, beneficial, and physiological outcomes for hGH neuroendocrine health and vitality can be expected from GHRP protocols such as those utilizing GHRP2Pro™. By using peptides such as GHRP2, in conjunction with other established antiaging interventions, then good physical and functional outcomes may be realized. References 1. Bowers CY. (2000) GHRP Historical Perspective Basic and Clinical. In: Human Growth Hormone Basic and Clinical Research. Contemporary Endocrinology, eds R. Smith, M. Conn, Humana Press, New York, page 17-43. 2. Bowers CY, Momany FA, Reynolds GA, Hong A. (1984) On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology, 114(5):1537–1545. 3. Raun K1, Hansen BS, Johansen NL Et al. (1998) Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol, 139(5):552-561. 4. Pandya N, DeMott-Friberg R, Bowers CY et al. (1998) Growth Hormone (GH)-Releasing Peptide-6 Requires Endogenous Hypothalamic GH-Releasing Hormone for Maximal GH Stimulation, J Clin Endo Metab, 83(4): 1186– 1189 5. Bowers, CY. (1998) Growth Hormone Releasing Peptide (GHRP). Cell and Mol Life Sci. 54(12):1316-1329. 6. Cella SG, Locatelli V, Poratelli M, et al. (1995) Hexarelin, a potent GHRP analogue: Interactions with GHRH and clonidine in young and aged dogs. Peptides, 16 (1):81-86. 7. Howard AD, Feighner SD, Cully DF, et al. (1996) A receptor in pituitary and hypothalamus that functions in growth hormone release. Science 1996, 273:947-977. 8. Lengyel AMJ (2006) From growth hormone-releasing peptides to ghrelin: discovery of new modulators of GH secretion. Arq Bras Endocrinol Metab [online]. 2006, vol.50, n.1 [cited 2019-11-11], pp.17-24. 9. Kojima M, Hosoda H, Date Y, et al. (1999) Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature, 402:656-60.

10. van der Lely AJ et al. (2004) Biological, Physiological, Pathophysiological, and Pharmacological Aspects of Ghrelin. Endocrine Reviews 25(3):426–457.

15. Rudman D, Feller AG, Nagraj HS et al. (1990) Effects of human growth hormone in men over 60 years old. N Engl J Med. 323(1):1-6.

16. Walker RF, Bercu BB (1998) Comparative effects of GHRH and GHRP2. JAAM 1:219-225, 1998 17. Spik K, Sonntag WE, (1989) Increased pituitary response to somatostatin in aging male rats: relationship to somatostatin receptor number and affinity. Neuroendocrinology 50:489-494 18. Kern A, Grande C, Smith RG. (2014) Apo-ghrelin receptor (apo-GHSR1a) regulates dopamine signaling in the brain. Front Endocrinol 5: 1-8. doi: 10.3389/fendo.2014.00129 19. Hansen BS et al. (2001) The Growth Hormone-Releasing Hormone Receptor: Desensitization Following Short-Term Agonist Exposure. Pharmacology & Toxicology, 88, 81–88. 20. Bilezikjian, L.-M., Seifert H, Vale W: (1986) Desensitization to growth hormonereleasing factor (GRF) is associated with downregulation of GRF-binding sites. Endocrinology 118:2045–2052. 21. Vance, M. et al. (1986) Dual effects of growth hormone (GH)-releasing hormone infusion in normal men: somatotroph desensitization and increase in releasable GH. J. Clin. Endocrinol. Metab. 62: 591–594. 22. Aleppo G, et al. (1997) Homologous down-regulation of growth hormone-releasing hormone receptor messenger ribonucleic acid levels. Endocrinology.138(3):1058-1065.

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23. Mitani M, Kaji H, et al. (1996) Growth hormone releasing peptide and GH releasing hormone stimulate GH release from subpopulations of somatotrophs. J Neuroendocrinol. 8(11):825-830. 24. Bowers CY, Granda R, Mohan S et al., (2004) Sustained Elevation of Pulsatile Growth Hormone (GH) Secretion and Insulin-Like Growth Factor I (IGF-I), IGF-Binding Protein-3 (IGFBP-3), and IGFBP-5 Concentrations during 30-Day Continuous Subcutaneous Infusion of GH-Releasing Peptide-2 in Older Men and Women. J Clin Endocrinol Metab 89:2290–2300 25. Pincus, S. M.; Gladstone, I. M.; Ehrenkranz, R. A. (1991). "A REGULARITY STATISTIC FOR MEDICAL DATA ANALYSIS". Journal of Clinical Monitoring and Computing. 7 (4): 335–345. doi:10.1007/BF01619355 26. Pincus SM. Approximate entropy as a measure of system complexity (statistic/ stochastic processes/chaos/dimension). Proceedings of the National Academy of Sciences of the USA 1991 88 2297–2301. 27. Pincus SM & Kalman RE. (1997) Not all (possibly) ‘random’ sequences are created equal. Proc Nat Acad Sci. 94:3513–3518. 28. Veldhuis JD, Pincus SM, (1998) Orderliness of hormone release patterns: a complementary measure to conventional pulsatile and circadian analyses Eur J Endo, 138:358–362

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11. Ferro P. et al. (2016) Structure-activity relationship for peptídic growth hormone secretagogues. Drug Test. Analysis, 9(1):1-5. 12. Walker et al. (1990) Oral activity of the growth hormone releasing peptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 in rats, dogs and monkeys. Life Sciences, 47:29-36. 13. Adis Editorial (2004). "Pralmorelin". Drugs in R&D. 5 (4): 236–239. doi:10.2165/00126839-200405040-00011 14. Graul, A I, Prous, JR (2006). "The Year's New Drugs: A Historical and Research Perspective on the 41 New Products that Reached their First Markets in 2005". Drug News & Perspectives. 19 (1): 33.

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SUPPLEMENTING FOR SPORTS PERFORMANCE

SPECIALIST SPORTS SUPPLEMENTS

The best way of describing it, is as a modulator of estrogen function, in other words, it restores a normal function of estrogen without excessive blocking of the beneficial effects of estrogen, and without overstimulation of its negative effects.

by Marios Kyriazis, M.D.

While DIM has been used in dealing with several types of cancers, it has a particular relevance to exercise, because estrogen and exercise have a mutually influencing relationship (Vieira-Potter 2015). For example, too much or too little estrogen in the body has been liked to a decreased level of physical activity (Gavin et al 2018). It is worth remembering that estrogen is not only found in women, but it is increasingly present in older men.

Since the dawn of time, primitive humans, and later competitive athletes have attempted to improve their performance by consuming a variety of substances. The use of nutritional supplements in improving sports performance is widespread, as athletes try to find ways to perform better without side effects or adverse reactions. Anybody who is interested in this field, however, should not approach it superficially, but must follow the suggestions of science and medicine. Many non-professional athletes believe that apart from training, they can enhance their performance by taking one or two products designed to release energy, or one or two products to enhance their metabolism. There is no point in taking a few supplements that you read about on the internet, and hope that you will suddenly experience dramatic endurance and stamina. The biology of sports performance is much more complicated than this, and in this article, I will discuss some aspects of the process. The discussion will examine some compounds, nutrients, or remedies that are supported by science and may be used under suitable supervision in a personalized way. In other words, each person may respond differently following supplementation of any kind, and it is necessary to tailor-made the supplement regime to suit that individuals and his/her needs. This is based on the more general principle of Personalized Medicine, that should be applied in all instances of supplementation, for any situation, illness or general health. 34

Estrogens and metabolism We know that, with age, estrogen metabolism changes, and this has an implication on bodily health. While estrogen function generally decreases with age, we are exposed to other environmental factors which may disrupt this process and, as a result, have an augmented estrogenic function, which is connected to increased incidence of some cancers. The entire process is very complex, but the overall aim is to balance excessive vs defective function of estrogen and to avoid estrogen toxicity. In this respect there are many studies which concentrate on estrogen disruptors, compounds that may interfere and modulate the different estrogenic pathways. There are over 450 estrogenic chemicals and estrogen disruptors (Kiyama 2015), which take part in estrogenic signaling and metabolism. One such compound is diindolylmethane (DIM) derived from indole-3-carbinol (I3C). This an ingredient of broccoli, cabbage, kale and other cruciferous (Brassica) vegetables.

Older women experience a decreased estrogen function, and older men have an increased estrogen function, bringing us to a situation where a 60-year-old man may have more estrogen in his body, compared to a 60-year-old woman. Therefore, products such as DIM which regulate and normalize estrogen function are useful in this respect. In practical terms, this estrogen balance is translated into stronger bones, regulated body fat, and optimal muscle mass, all of which are useful in any athlete. The dose is different depending on the condition being addressed. For example, in cancer a dose of 8 mg per Kg of weight has been used, whereas in normal situations appropriate for in healthy sport situations, a dose is 1 mg to 2 mg per Kg of weight.

Oxide comes in. This is a colorless gas which helps widen the arteries, among other actions. Not many people realize that Nitric Oxide (NO) is a free radical, which though, in small amounts, has proven benefits. Two amino acids which can help release NO by the body are arginine (best obtained from pumpkin) and citrulline (for example, from watermelon). Arginine works by blocking an enzyme that destroys NO (therefore effectively increasing NO presence) (Kittel 2014), whereas citrulline increases arginine actions, (Figuero et al. 2017). The authors of this study quote: • The beneficial vascular effects of L-citrulline/watermelon supplementation may stem from improvements in the L-arginine/nitric oxide pathway. • Reductions in resting blood pressure with L-citrulline/ watermelon supplementation may have major implications for individuals with prehypertension and hypertension. L-Citrulline supplementation, but not acute ingestion, have shown to improve exercise performance in young healthy adults

So, we see that these two amino acids used in combination (and there exist commercial products such as NitricPro™), may contribute to a better exercise performance.

Nitric Oxide and blood circulation A good physical performance does not only depend on muscular function, but also on how well the muscles are oxygenated and on how fast the metabolic toxins are eliminated from the muscle. In other words, on how efficient the blood circulation is one way to assure good blood circulation is to help improve the flow of blood through the blood vessels, and here is where Nitric 35

SUPPLEMENTING FOR SPORTS PERFORMANCE

• Note: NO nitric oxide is a gas found within the blood that is made in the endothelial layer, found in the lining of blood vessels.

The role of NO in sports was examined in a recent study (Jacob et al. 2018), where it was shown that oral supplementation with compounds that can increase NO action, is reflected in higher concentrations of NO radicals in the serum and saliva of the user. By the way, there are several other compounds which can increase NO concentrations, such as polyphenols, flavones, saponins etc. However, the combination of citrulline and arginine seems to be the best; NO is not only useful in sport, but also in promoting overall vascular health and repairing agingrelated damage. The role of Phenethylamine as a stimulant Another very important factor in maintaining physical fitness is cognitive health. An athlete or anyone who exercises for general fitness need to have good motivation, alertness and generally to be mentally stimulated. This is the reason why some athletes choose to take, not only supplements to boost physical performance, but also supplements which have a positive effect on the brain. Phenethylamine (PEA) is one such compound. It is a natural monoamine alkaloid, with stimulating effects on the brain. Basically, it regulates neurotransmission, either by blocking excessive neurotoxins, or by stimulating better transmission of information from neuron to neuron. One food that contains PEA is chocolate, but it is also available as a dietary supplement. Apart from its use in sports, it is also used to reduce the effects of depression, and generally to keep the brain alert. Some people also use it in order to achieve better erection, or for weight loss purposes. 36

SUPPLEMENTING FOR SPORTS PERFORMANCE

Like all compounds mentioned here, it should only be used under expert supervision because it is not suitable for everybody. There is not enough reliable information about the recommended dose, and this is another reason to consult a professional before using it. • Some other supplements and compounds used in sports performance are:

Vitamin C It can help in maintaining good health of the heart. This is best obtained from acerola cherries, and preferably not synthetic. In a clinical trial, scientists from Taiwan wanted to see if high dose of vitamin C (together with vitamin E) has any effect on exerciseinduced muscle damage. Eighteen elite athletes took part. Half of those were given 2000 mg of vitamin C and 1400 U vitamin E a day for 4 days. The other half were given placebo. They found that inflammation and other toxicity markers (myoglobin, creatine kinase, and hemolysis) were significantly lower in the active group (Chou et al. 2018). Therefore, it was shown that vitamin C supplementation reduces exercise-induced tissue damage, both during and after a heavy sporting activity. Ribose It is an energy booster. This is a natural form of sugar that takes part in the metabolism of adenosine triphosphate (ATP) which provides energy during muscular actions. During intense exercise, ATP levels may get severely depleted, and recovery may take several days. This effect is more pronounced in untrained people who decide to exercise intensely for a while. Athletes use ribose both before exercise to increase ATP, and after to replace lost ATP. It prevents muscle cramps, stiffness and pain after exercise.

In a study, researchers wanted to see if the benefits of oral ribose supplementation translate into practical benefits in athletes (Seifert et al. 2017). Here are the results, as stated by the authors of the study (summarized): The study was a double blind, crossover study in 26 healthy subjects compared 10 g/day of ribose to 10 g/day of dextrose (as control). All subjects completed 2 days of loading with either ribose or dextrose, followed by 3 additional days of supplementation and during these 3 days of supplementation, each subject underwent 60 minutes of high intensity interval exercise in separate daily sessions. Ribose supplementation resulted in maintenance in exercise performance, as well as lower levels of the rate of perceived exertion and creatine kinase (an enzyme that increases following muscle injury). There were no observed benefits with dextrose supplementation.

MSM (methylsulfonylmethane) If exercise is strenuous, it may cause pain, muscle soreness and increased production of free radicals and inflammation-related toxins. Some athletes are using MSM to prevent these effects. MSM is a sulfurbased nutritional supplement that reduces inflammation and pain following exercise. In a clinical trial (van der Merwe 2016) active men were given MSM supplementation (3 g daily) or placebo for 4 weeks and then asked to perform strenuous exercise. It was found that the group that took the MSM supplements had lower concentrations of inflammation markers in their blood, compared to the placebo group (Figure 1). The authors concluded that: Strenuous exercise causes a robust inflammatory reaction that precludes the cells from efficiently responding to additional stimuli. MSM appears to dampen the release

of inflammatory molecules in response to exercise, resulting in a less incendiary environment, allowing cells to still have the capacity to mount an appropriate response to an additional stimulus after exercise. of free radicals and inflammation-related toxins. Some athletes are using MSM to prevent these effects. MSM is a sulfurbased nutritional supplement that reduces inflammation and pain following exercise.

Carnosine and beta-alanine The di-peptide Carnosine (beta-alanine, L histidine) has been used in the field of sports endurance (and aging) for several decades. It is highly concentrated in muscle where it acts as an intracellular pH buffer. In this way it is used in order to increase high-intensity sports performance (Sale et al. 2013). Betaalanine supplementation increases the levels of carnosine in the muscle. For example, (de Andrade Kratz et al. 2017), in a clinical trial it was shown that when beta-alanine (carnosine) is given as an oral supplement for 4 weeks it improved high intensity performance in judo athletes, and it may www.antiaging-systems.com

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SUPPLEMENTING FOR SPORTS PERFORMANCE

also be of benefit in rowing sports (Furst et al 2018). For these reasons, carnosine is very popular in sports because it can delay fatigue and improve endurance (Hoffman et al 2018). But carnosine has also other beneficial effects which can be useful in sport. Namely, it may help improve resistance to stress and enhances certain brain functions that are useful in both competitive athletes and those exercising for everyday general health.However, there is one issue here that can be of relevance. There are several discrepancies in the effectiveness of carnosine, and these depend on the actual sport or physical activity on which it is being tested. Benefits have been found in specific examples of sports and these are: cycling race of 4 km, rowing race of 2,000 m, swimming race of 100 and 100

200 m, combat modalities, and water polo (Brisola et al 2019). In any case, in another twist, carnosine in association with zinc has been found to regulate gut permeability. This can be important in athletes because we know that heavy exercise results into increase passage of toxins from the gut to the blood, and this may cause heat stroke or abdominal symptoms (Danison et al. 2016). Zinccarnosine was tested on athletes, either on its own or in association with colostrum. It was shown that Zinc -carnosine taken alone or with colostrum, increased epithelial resistance, which means that the risk of adverse effects such as heat stroke is prevented.

In a review of the actions of beta-alanine, it was concluded that it is a supplement that can increase performance at a very high level (Blancquaert et al. 2015). Carnosine regulates intramuscular calcium, and it has anti-glycator and antioxidant properties. Overall, it plays an important role in muscle physiology. The International Society of Sports Nutrition has concluded that (Trexler et al. 2015) (Figure 2): 1. Four weeks of beta-alanine supplementation (4-6 g daily) significantly augments muscle carnosine concentrations, thereby acting as an intracellular pH buffer 2. Beta-alanine supplementation currently appears to be safe in healthy populations at recommended doses 3. The only reported side effect is

Relative Effect

(pg/ml)

600 400

Baseline

Placebo MSM

24 Time (hours)

Baseline

Placebo MSM

(a)

100

24 Time (hours)

Smith-Ryan et al., 2012 Men 110% Jagim et al., 2013 Men 115%

100

Jagim et al., 2013 Men 140% Hill et al., 2007 Men 110%

90 80

(b)

Placebo MSM

24 Time (hours) (c)

500

Baseline Placebo MSM

24 Time (hours)

(d)

Figure 1. Dampening of the inflammatory effect through administration of MSM, over time. The beneficial effects of MSM are clearly better than placebo. Source: J Sports Med (Hindawi Publ Corp). 2016; 2016: 7498359. Copyright © 2016 M. van der Merwe and R. J. Bloomer. Distributed under the Creative Commons Attribution License. 38

150

200

250

300

Effects of Beta-Alanine Supplementation on Time to Exhaustion (8-25 mins)

350

Smith-Ryan et al., 2014 (a) GXT Men/Women Zoellxx et al., 2007 GTX Men

120 Relative Effect

(pg/ml)

(pg/ml) Baseline

100

Time (Seconds)

130

Smith-Ryan et al., 2012 Men 90% Smith-Ryan et al., 2012 Men 100% Smith-Ryan et al., 2012 Men 110% Smith-Ryan et al., 2012 Men 90% Smith-Ryan et al., 2012 Men 100%

110

1000

120

200 0

130

800

Effects of Beta-Alanine Supplementation on Time to Exhaustion (0-6 mins)

1000

paraesthesia (tingling), but studies indicate this can be attenuated by using divided lower doses (1.6 g) or using a sustainedrelease formula Daily supplementation with 4 to 6 g of beta-alanine for at least 2 to 4 weeks has been shown to improve exercise performance Beta-alanine attenuates neuromuscular fatigue, particularly in older subjects Combining beta-alanine with other single or multi-ingredient supplements may be advantageous when supplementation of beta-alanine is high enough (4-6 g daily) and long enough (minimum 4 weeks) More research is needed to determine the effects of beta-alanine on strength, endurance performance beyond 25 min in duration, and other health-related benefits associated with carnosine

Ghxxxxxxx et al., 2012 Men 110%

110

Stout et al., 2012 Men 90%

100

Smith et al., 2012 Men 100%

90 80 70

500

600

700

800

900

1000

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1300

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Time (Seconds)

Figure 2: A review of the effects of beta-alanine supplementation on time to exhaustion (TTE) lasting (A) from 0 to 6 min, and (B) lasting from 8 to 25 min. Source: Trexler et al. 2015

SUPPLEMENTING FOR SPORTS PERFORMANCE

In a more recent study, the benefits of betaalanine on exercise performance have been examined further (Saunders et al. 2017). Over 1400 individuals were studied with respect to exercise duration, performance and amount of beta-alanine consumed. The conclusion was that beta-alanine had a significant overall benefit, although this also depends on the actual exercise modality chosen by the participant. By the way, it was suggested that carnosine and beta-alanine supplementation may be of use to vegetarian athletes who do not eat meat, (which is rich in these two compounds). Here, a word of warning. It is best to remain within recommended dosage for each compound used, and to consider that combinations of nutrients or supplements may cause not only potentiation of their normal effects, but also side effects. Therefore, it is best to work with a qualified professional in finding the right combination and dose. Conclusion We see that there are several ways to maintain our physical fitness, and to increase this fitness to the level of a competitive athlete. However, we need to be careful in choosing the various supplements in a way that it is suitable for our own circumstances, and not just take something that our friend is taking. It is also important to note that the physical exercise routine needs to also be appropriate for our own situation, to maximize our aims. And here, we must ask ourselves; “what is our aim in this respect? Is it to be physically strong? To be a body builder? Or to become a competitive athlete? Or just to be in a generally fit state which helps reduce the effects of age?” Each situation has different requirements.

SUPPLEMENTING FOR SPORTS PERFORMANCE

articles in this issue, will help overall, but their use should be targeted specifically to your own needs.

Disclaimer: All educational information is provided under the IAS terms and conditions which may change without notice. Restrictions may apply in some countries.

References 1. Blancquaert L, Everaert I, Derave W. Beta-alanine supplementation, muscle carnosine and exercise performance. Curr Opin Clin Nutr Metab Care. 2015 Jan;18(1):63-70 2. Brisola, GMP and Zagatto, AM. Ergogenic effects of β-alanine supplementation on different sports modalities: strong evidence or only incipient findings? J Strength Cond Res 33(1): 253-282, 2019 3. Chou CC et al. Short-Term High-Dose Vitamin C and E Supplementation Attenuates Muscle Damage and Inflammatory Responses to Repeated Taekwondo Competitions: A Randomized Placebo-Controlled Trial. Int J Med Sci. 2018 Jul 30;15(11):1217-1226 4. Davison G, et al. Zinc carnosine works with bovine colostrum in truncating heavy exercise-induced increase in gut permeability in healthy volunteers. Am J Clin Nutr. 2016 Aug;104(2):526-36 5. de Andrade Kratz C et al. Beta-alanine supplementation enhances judo-related performance in highly trained athletes. J Sci Med Sport. 2017 Apr;20(4):403-408 6. Figueroa A, Wong A, Jaime SJ, Gonzales JU. Influence of L-citrulline and watermelon supplementation on vascular function and exercise performance. Curr Opin Clin Nutr Metab Care. 2017 Jan;20(1):92-98 7. Furst T, Massaro A, Miller C, Williams BT, LaMacchia ZM, Horvath PJ. β-Alanine supplementation increased physical performance and improved executive function following endurance exercise in middle aged individuals. J Int Soc Sports Nutr. 2018 Jul 11;15(1):32 8. Gavin KM, Kohrt WM, Klemm DJ, Melanson EL. Modulation of Energy Expenditure by Estrogens and Exercise in Women. Exerc Sport Sci Rev. 2018 Oct;46(4):232-29 9. Hoffman JR, Varanoske A, Stout JR. Effects of β-Alanine Supplementation on Carnosine Elevation and Physiological Performance. Adv Food Nutr Res. 2018;84:183-206 10. Jacob J, Gopi S, Divya C. A Randomized Single Dose Parallel Study on Enhancement of Nitric Oxide in Serum and Saliva with the Use of Natural Sports Supplement in Healthy Adults. J Diet Suppl. 2018 Mar 4;15(2):161-172 11. Kittel A, Maas R. Pharmacology and clinical pharmacology of methylarginines used as inhibitors of nitric oxide synthases. Curr Pharm Des. 2014;20(22):353047 12. Kiyama R, Wada-Kiyama Y. Estrogenic endocrine disruptors: Molecular mechanisms of action. Environ Int. 2015; 83:11-40

13. Sale C et al. Carnosine: from exercise performance to health. Amino Acids. 2013 Jun;44(6):1477-91 14. Saunders B et al. β-alanine supplementation to improve exercise capacity and performance: a systematic review and meta-analysis. Br J Sports Med. 2017 Apr;51(8):658-669 15. Seifert JG, Brumet A, St Cyr JA. The influence of D-ribose ingestion and fitness level on performance and recovery. J Int Soc Sports Nutr. 2017 Dec 20;14:47

16. Trexler ET, et al. International society of sports nutrition position stand: BetaAlanine. J Int Soc Sports Nutr. 2015 Jul 15;12:30 17. van der Merwe M, Bloomer RJ. The Influence of Methylsulfonylmethane on Inflammation-Associated Cytokine Release before and following Strenuous Exercise. J Sports Med (Hindawi Publ Corp). 2016;2016:7498359 18. Vieira-Potter VJ, Zidon TM, Padilla J. Exercise and Estrogen Make Fat Cells "Fit". Exerc Sport Sci Rev. 2015 Jul;43(3):172-8

The compounds and supplements mentioned here, together with others discussed in other 40

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Youth Gems® have not been used on animals and are suitable for vegetarians Disclaimer: All educational information is provided under the IAS terms and conditions which may change without notice. Restrictions may apply in some countries. (*plus S&H).

The world’s first OSCN supplement is a four part kit that is easily and quickly made in a glass of water for immediate use- plus it has no taste nor smell.

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SPOTLIGHTS

1ST LINE™ - the first line of immunity Professor Paul Clayton reported in the Aging Matters magazine No1, 2012, that ‘the age of antibiotics is coming to an end.’ This has been a concern for some time as antibiotics becomes less effective and can’t be relied upon as they were in the past. What’s more, antibiotics do not destroy viruses, and when it comes to effective antivirals there are very few choices indeed. OSCN A British chemist by the name of Richard Steed was concerned how chlorine was being in food- as it is sprayed onto salads. It kept the vegetables free of bacteria, but it is hardly a healthy option for the consumers. He investigated nature and found that oxythiocynate ions, otherwise known as OSCN are present in tears, saliva and mother’s milk and appear to destroy many pathogens including viruses, since OSCNs are literally the first line of immune defence. Thereafter, he created the world’s first supplement containing OSCN molecules. Soon it was realised that they also had massive health implications. An OSCN kit An OSCN kit OSCNs have a very short half-life, something like 30 minutes, which is why you have never seen them presented in a supplement before.

SPOTLIGHTS

But 1ST LINE™ is different because it is a kit containing the active and 3 enzymes to make up the supplement in a glass of water for consumption straight away. It is easy to use, simply add the 4 agents in the right order (marked 1-2-3-4), stir and drink. 1st Line™ has no smell or flavor. Doing so creates 25 mg of OSCN, the equivalent to what a healthy body produces in a day. How to use Obviously, there are a plethora of infections out there, but on a simple level take a 1st Line™ dose at the first sign of infection and repeat the dose for a day or two afterward, as necessary. For maintenance, some individuals like to take one dose of 1st Line every month in order to keep the ‘body burdens’ low.

can ‘disorganise’ healthy cells by crashing around- a bit like bumper cars at a fayre. The free radical theory of aging was first proposed by Professor Denham Harman in the late 1950s and it helps to explain the degenerative processes that occur during aging. Hierarchy There are several levels of free radicals, and the worst of them are the superoxide and the hydroxyl free radicals. Neutralisation of ‘higher level’ free radicals can create a plethora of lower level free radicals, so it is important to try and impact every stage, but of course to particularly target the most destructive free radicals.

Dose ACF228® has been designed as a one capsule per day formula.

BEC5® curaderm - a truly amazing skin cream The story of BEC5® cream is remarkable. When it is told people often can’t believe it- and when they realise the cream has been available for decades, they become flabbergasted! How so? Because this naturally derived skin cream has been shown to be virtually 100% effective in removing basal and squamous cell skin cancers (sic).

Potency In the ACF228® formula there are numerous unique molecules like catalase and especially NDGA within ACF228®. Synergy ACF228® has numerous synergistic agents that have been designed to help neutralise every level of free radicals, no other single product has been in-vivo designed- each ACF228® capsule contains: Ingredients

ACF228 - the ultimate free radical scavenger ®

The ACF abbreviation means ‘antioxidant complete formula’ and 228 because it was Dr. Richard Lippman’s 228th formula that proved to be very effective. Dr. Richard Lippman was nominated for the Nobel Prize in medicine for his work in measuring free radical activity in-vivo; in other words what happens within the human body. The result of that work led to the incredibly comprehensive formula known as ACF228®. Free radicals Free radicals are unstable molecules that can be created ‘naturally’ within the body and they

Quantity

N-acetylcysteine

100 mg

L-methione

100 mg

Di-indole-methane

83 mg

L-carnosine

83 mg

Deodorised garlic

50 mg

Trans resveratrol

17 mg

Vitamin B6

17 mg

NDGA

3 mg

Potassium iodide

3 mg

Iodine

2.5 mg

Methylfolate

800 mcg

Chromium picolinate

120 mcg

Selenium

100 mcg

Vitamin B12 Catalase

10 mcg 0.025 mg

History It all starts on the island of Vanuatu in the South Pacific, when a young man by the name of Bill Edward Cham (BEC) walked around the fields and noticed horses and cows rubbing themselves against a local plant called the Devil’s Apple, (a member of the eggplant family). Asking the farmers why they did this, he learnt that the animals had skin lesions and the rubbing helped clear them up. As Dr. Cham was training to be a biochemist this fascinated him and over 20+ years his research revealed a remarkable secret. Skin cancers He identified that the active ingredient was

SPOTLIGHTS

solasdines and that it ‘ate away’ a ribose coating on cancer cells that isn’t present on healthy cells. The result is that the cancer cells are exposed to the immune system as ‘nonself’ cells, then the natural process of apoptosis is induced and then the body rids itself of the cancer cells. Documented history Many journals, particularly those in Australasia have published these studies and numerous magazines around the world have divulged this. Two excellent books on this subject are; the eggplant cancer cure and Curaderm a noninvasive medication for skin cancer. Application BEC5® cream is applied topically to SCC and BCC lesions twice a day and covered with a micropore. The typical treatment time is between 6 to 12 weeks. So why hasn’t this cream, (that avoids the need for surgery in most cases) not become famous and mainstream? The answer is simple, the active agent is natural and can’t be patented and therefore the current medical system will not promote it. Note BEC5® is not suitable for melanoma cancers.

CanC™ Eye-drops - a breakthrough for cataract 46

SPOTLIGHTS

Can-C™ eye-drops are the original formula containing n-acetylcarnosine (NAC), a natural di-peptide that has potent anti-glycating and antioxidant properties to prevent lipid peroxidation. Clinicals Patients who placed 2-drops of Can-C™ into their eyes twice daily for a 5/6-month period reported: An improvement in their visual acuity (90%) An improvement in the clarity of their lens (88.9%) There have been numerous reports of cataract shrinkage and even disappearance with documented evidence that Can-C™ eyedrops remain effective (and safe) more than 24-months later. Actuals The most commonly expressed initial reports are that glare is significantly improved, (for example night driving is easier) and color perception is enhanced. Most importantly, is an ability to read eye charts clearer, due to the better transmissivity of the lens. Broad spectrum Evidence is mounting that Can-C™ is efficacious for many conditions including: Cataracts (particularly the senile version) for both humans and dogs Glaucoma Presbyopia Eye strain Ocular inflammation Blurred vision Vitreous opacities and lesions Diabetes mellitus complications Contact lens comfort Dry eye syndrome

your mouth), then it is likely that centrophenoxine will be an aid; helping to bring clarity and flow to speech and thought. Doses A typical dose for the ‘average’ person is 250 mg once or twice daily.

Centro-PRO™ - improving mental recall speed Centro-Pro™ capsules contain centrophenoxine, (pronounced, centrow-fen-ox-in) and it is a classic ‘nootropic.’ History Centrophenoxine can increase acetylcholine levels in the brain. It is also very effective in reducing lipofuscin levels, this component is part of Alzheimer brain plaques. Accordingly, this reduction of membrane toxins like lipofuscin aids cellular communication. This is a key feature of the membrane hypothesis of aging- which has been published by Professor Nagy. Thus, centrophenoxine is useful for those concerned about Alzheimer’s, but in addition, centrophenoxine has been noted to help enhance and protect the performance of an healthy, aging individual. General cognitive benefits Classifying the precise benefits of the various nootropics can be tricky. Many people simply refer to their ailing cognitive facilities as “memory loss.” However, a quick breakdown of that statement requires further evaluation- in order to determine the precise nature of the problem. In such a case, centrophenoxine is perhaps best suited to the issue of recall speed. So, If your speech appears to be full of “ums” and “ers” (whilst your brain tries to catch up with

Dep-PRO™ - for focus and concentration Dep-Pro™ contains deprenyl (also known as selegiline), it was created in the 1960s by Professor Joseph Knoll to treat Parkinson’s patients since deprenyl improves dopamine levels. Significant longevity studies Professor Knoll’s experiments with rats also produced the most incredible longevity benefits. When the animals were fed deprenyl in their food, they lived so much longer that even after the last nontreated rat died, the first of the deprenyl treated rats was yet to die! (Note: importantly, these results were verified independently in another study not undertaken by Professor Knoll). Based on this research, Dean, Fowkes and Morgenthaler, published in the book, Smart Drugs and Nutrients, that the loss of dopamine in aging humans can be mapped against both the development of Parkinson’s and even death.

SPOTLIGHTS

Mode of action For a long time deprenyl has been described as a MAO-b inhibitor, that it to say that is prevents this enzyme from destroying dopamine, leading to its improvement. Later, Professor Knoll noted that deprenyl also raises PEA levels and catecholamine sensitivity. Typical responses Deprenyl can assist: The treatment of Parkinson’s and other dementias. Male libido enhancement. Boost metal energy levels especially focus and attention. Life expectancy, at least in animals. Dosing Parkinson’s patients use high doses, but healthy aging adults typically use 1 mg to 3 mg per day, this is dependent on age and need. Note These doses do not consider synergy with other dopamine enhancing agents and, in such cases, would have to be adjusted accordingly.

SPOTLIGHTS

biological age-markers by as much as 20-years! Specifically, he noted that they had improved the patients’ skin, hair, muscle mass, decreased fat levels and enhanced levels of stamina, strength and well-being. The issue with GH, (other than its expense), is that it does have to be injected to be effective; this is because it is a 191-chain of aminoacids so it simply can’t be absorbed via any other route. Furthermore, many countries have classified GH injections as a controlled substance, partly because of its anabolic actions. GHRPs Thankfully, Dr. Walker’s research has shown that the use of GHRPs, (growth hormone releasing peptides) have a much safer profile whilst enjoying many of the same benefits. GHRPs can be sublingually and intranasally, and thus avoid the need for needles. The GHRP feedback loop means that they cannot cause the pituitary to down-regulate production of GH. GHRPs are not controlled substances. Rather than inducing a spike of GH in the blood, GHRPs augment GH naturally into the blood. Synergy The main GHRP is GHRP2 which can be used sublingually, in addition there is also intranasal Sermorelin- this is the precursor to GH, (the first 29-aminoacids). Its function is to release existing stores of GH from the pituitary, rather than encourage more production. Dr. Walker suggests that combining sermorelin with GHRP2 can elicit up to a 5x greater quantity of GH into blood.

GHRPS - an alternative to growth hormone injections Dr. Daniel Rudman’s research in the late 1980s concluded that elderly patients using Growth Hormone (GH) could reverse their

Summary GHRPs have created a genuine alternative to GH injections; they are simpler and easier to use and at the same time they have a safer profile.

Lowering the blood cholesterol, triglycerides and beta lipo-proteins. Reducing the development of atherosclerosis. Reducing insulin levels. Increasing hypothalamo-pituitary sensitivity. Improving the cellular immunity. Enhancing the activity of anti-cancer drugs. Suppressing the growth of some tumors. Increasing the maximum life span of animals.

Met-PRO™ improving the insulin sensitivity Met-Pro™ contains metformin, a diabetes type-2 treatment that has been used for many decades. Metformin differs from other insulin medications, since rather than increasing the production of insulin from the pancreas, it improves the sensitivity of the receptor site to insulin; in other words you ‘get more bang for your buck’ by improving the performance of insulin to peripheral tissues, (like muscles). This has interesting implications for aging since the neuroendocrine theory of aging teaches us that it is the loss of sensitivity at receptors that is a major ‘fault’ in aging. Weight loss Persons who utilise metformin, (even those who may be pre-diabetic or otherwise not affected), have often noted that it helps them to maintain a healthy weight with lower fat levels etc.

Miles Metformin is a milestone, since it is the first medicine in the world to be granted an FDA approved study for antiaging titled; metformin in longevity study. Note Metformin does inhibit the uptake of vitamin B12, so in order to counter potential side-effects it is recommended to supplement with B12 at the same time.

MZS™ - because not all melatonins’ are created equal

Melatonin is produced at night by the pineal Antiaging gland to help regulate the circadian rhythm. As Dr. Ward Dean has stated that; “metformin is one we age, the amount of melatonin we produce of the most promising antiaging, life-extending declines and it results in many persons having a drugs available.” lower quality of sleep. It’s a profound statement, but it is predicated on MZS™ has been formulated by the world’s the amazing range of metformin’s clinical effects foremost melatonin expert- Dr. Walter Pierpaoli, which include: his MZS™ (melatonin, plus zinc and selenium),

SPOTLIGHTS

is totally unique since it is designed to mimic the natural night peak of melatonin- leaving you refreshed and alert the following day. What does melatonin do? Melatonin is vital to protect our hormonal system, regulate immunity and repair our body’s cells. It is commonly used by shift workers and to treat jet-lag and age-related sleep disorders, but its abilities go far beyond its sleep improvement properties. Antioxidant effects Melatonin is an extremely effective antioxidant; in fact, on a molecule to molecule basis, melatonin has proved to be more efficient in neutralizing toxic hydroxyl-radicals than the two well-known free radical scavengers, glutathione and mannitol. Lowering the blood cholesterol, triglycerides and beta lipo-proteins. Reducing the development of atherosclerosis. Reducing insulin levels. Increasing hypothalamo-pituitary sensitivity. Improving the cellular immunity. Enhancing the activity of anti-cancer drugs. Suppressing the growth of some tumors. Increasing the maximum life span of animals. Melatonin and longevity Melatonin’s effect on longevity is well documented. Laboratory tests on animals have demonstrated that melatonin increased their lifespans by 20%. MZS™ and ARMD Age related macular degeneration comes in two forms, wet and dry and it is a notoriously difficult disorder to treat- linked to blindness. In a 24-month study, (NY Academy of Science, 2005, 1057:384-392) on 100 patients showed that after 3 months, the majority of patients taking 3 mg of MZS™ nightly had halted the progression of their AMRD and at 6 months many reversed their ARMD. Remarkably this was true for both the wet and dry forms!

SPOTLIGHTS

Dr. Pierpaoli’s melatonin Dr. Pierpaoli’s MZS™ formula mimics the pineal gland’s release of melatonin when it is taken between 9-11 PM because it releases between 1-3 AM, the natural night-peak of melatonin in blood.

Nature’s Marvels™ - how peptide bioregulators in food are gene switches Professor Vladimir Khavinson is the President of the European Academy of Gerontology and Geriatrics. In the 1980’s he was a Colonel in the Soviet Union military medical corps. He and his team were approached by Kremlin who wanted a way to protect their troops from various problems. The research uncovered a remarkable link between short-chain peptides and DNA. Basically, short-chain peptides- in food act as gene specific switches; they termed them ‘peptide bioregulators.’ This former military secret is now available and to-date 21 have been identified to assist various organs, glands and tissues. These peptides, unlike proteins, can enter through the stomach and a comprehensive list of patents, confirms that each of the peptide bioregulators interact with DNA - activating repair and regenerative processes. Original materials from the trials Nature’s Marvels™ are the English packaged and approved peptide bioregulators from Professor Khavinson, (all bovine sourced).

Here is the complete list: 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

Adrenal Bladder Blood vessels Bone marrow Brain (CNS) Cartilage Heart Kidney Liver Lung Muscle Ovaries Pancreas Parathyroid Pineal Prostate Retina Stomach Testes Thymus Thyroid

Dosing A typical program is as follows: Start with an intensive course of 2-capsules once a day for 30-days. Thereafter, use 2-capsules once a day for 10-days, repeat every 1, 2 or 3 months.

Oxy-PRO™ - for passion and sex

Oxy-Pro™ contains oxytocin, a hormone produced by the hypothalamus but excreted via the pituitary gland. Its orthodox role is to help women give birth, since the large dose that’s injected helps relax the uterus and alleviates the passage of the child. Meanwhile, Dr. Thierry Hertoghe’s book; ‘passion, sex and longevity, the oxytocin adventure’- has shown it to have many other roles. The love hormone Oxytocin has been dubbed ‘the love hormone’. This is because oxytocin can induce feelings of bonding and care. Not just between individuals, but even with animals too! Oxytocin measurements have been taken between lovers, friends, relatives, parents and their children etc. From those results, it has been noted that oxytocin levels are higher when they are in their presence. Mothers naturally bond with their children, but even men, (especially those who experience the live birth), express their emotions as wanting to care and protect their offspring, these effects may be attributable to the release of oxytocin, hence triggering the bond. On the other side of the coin, psychopaths are notoriously low in their oxytocin levels, which may be a cause of their uncaring feelings towards other humans. The pain and orgasm connection Fibromyalgia can be a very debilitating disorder with a lot of pain, sometimes constant for those who suffer with it. In women with fibromyalgia it was noted that when they were experiencing an orgasm, they felt no pain at all. Later, it transpired that women undergo a burst of oxytocin during orgasm. Trials were undertaken to see if oxytocin supplementation could alleviate the pain of fibromyalgia, there was some success, but the side effect noted was that those women now enjoyed multiple orgasms! This was a fact picked up on by the popular press and is

SPOTLIGHTS

probably singularly the action most responsible for bringing oxytocin into the public gaze.

Pira-PRO™ - the original nootropic Nootropic is a term meaning ‘towards the mind’ and they were originally designed for senile dementias, but now they have become popular for aging individuals to enhance their mental and cognitive processes. Ward Dean, M.D. has highlighted these facts in his ‘Smart Drug’ series of books; ever since then the term ‘smart drugs’ has become mainstream. Piracetam, the original Pira-Pro™ contains piracetam and piracetam was the first nootropic developed by Dr. Giurgea at UCB in the 1960s. Originally, it was used for travel and altitude sickness, but shortly afterward people realised that piracetam had positive effects on cognition. What does piracetam do? Piracetam is used for a wide range of conditions. For example, it has been shown to improve attention levels and memory retention. Piracetam can slow down ‘senile involution.’ In other trials, piracetam has improved memory consolidation in those suffering from ‘agerelated memory impairment.’

SPOTLIGHTS

Piracetam has aided patients recovering from strokes, in-particular improving post stroke speech impairment (aphasia). Another use has been for acute and chronic cerebral ischaemia, (decreased blood flow to the brain). Piracetam has even increased neuronal activity in the brain when measured with EEG. For normal individuals, piracetam can enhance idea creation and the ability to ‘see things through.’ In other words, to have ideas and then be able to bring them to fruition. The level of clarity piracetam induces is often described as; “the fog has lifted.” How does piracetam work? Piracetam’s key method of action is upon the Corpus Callosum, the region of the brain that links the two hemispheres. Many experts believe this enables piracetam users to channel greater brain potential by connecting the logical side of the brain with the creative side. This could be described as a Yin and Yang effect.

The thyroid gland The thyroid controls the body's metabolism, (the rate at which it burns calories for energy) and the body's utilization of fat; so a decline in thyroid function, can result in poor concentration, confusion, memory problems, cold hands and feet and weight gain. Other conditions triggered by an underactive thyroid are painful musculoskeletal issues that affect tendons, muscles and ligaments.

Publications for antiaging, preventative and regenerative health enthusiasts

Do I need a thyroid supplement? A doctor can check your blood levels, but a simple method is to take your body temperature when you wake in the morning. It should be in the range of 97.8 to 98.2 degrees Fahrenheit. If it is regularly lower than 97.8 F you could be hypothyroid and if regularly higher than 98.2 F then hyperthyroid. Synthetic vs. natural thyroids Synthetic thyroids typically only contain T3 or T4, but natural thyroids (like Armour® etc.) are of porcine origin and contain the full spectrum of T1, T2, T3 and T4 thyroid hormones. Converting between the two The table provides a helpful guide to the conversion rates for those wishing to switch from synthetic thyroids to natural versions. As always, we recommend consulting with a physician before making changes to your health program.

Thyroids - supporting the hypothyroid epidemic Dr. Broda Barnes estimated that 40% of adults are deficient in thyroid hormones. As the thyroid gland is of pivotal importance, a lack of its function can affect a wide variety of age-related health disorders. Ergo, supplementation can have many positive effects.

Dose of Desiccated Thyroid (Grains)

Equivalents (mg)

Dose of T3 (Lithytonine) (mcg)

Dose of T4 (Levothyroxine) (mcg)

0.5

12.5

100

130

200

300

260

100

400

325

125

500

www.thelongevity.store 53

ANTIAGING SYSTEMS

ANTIAGING-SYSTEMS.COM www.antiaging-systems.com is your comprehensive resource for information about all the leading commercially available antiaging, preventative, and regenerative products available today. Visit www.antiaging-systems.com and find articles, videos, audio-files, all referenced with a guide of where to obtain your needs. Currently the site covers topics related to all the following products: BOOKS Atlas of Endocrinology V2 by Thierry Hertoghe, MD Cataract Cure by Marios Kyriazis, MD Eyesight Saviors by Marios Kyriazis, MD Great Teeth for Life by Brian Halvorsen, BDS Melatonin, the Key of Life by Walter Pierpaoli, MD

Natural Skin Cancer Treatments by Bill Cham, PhD Passion, Sex & Oxytocin by Thierry Hertoghe, MD Patient Hormone Handbook by Thierry Hertoghe, MD Peptide Bioregulator Revolution by Dr. Kyriazis

Peptides in the Control of Ageing by Prof. Khavinson Physician Hormone Handbook V2 by Thierry Hertoghe, MD Reversing Physical Aging V1 by Thierry Hertoghe, MD Testosterone Therapy for Real Gentlemen by Dr. Hertoghe

DIAGNOSTICS Bio-Clip™ CUFF

Foodsafe®

GHRPS GHRP2 (GHRP2-Pro™)

Sermorelin (Serm-Pro™)

Nitric-Pro™ Sleep-Pro™ Vitamin B12 (B12-Pro™)

PEPTIDE BIOREGULATORS Adrenal (Glandokort®) Bladder (Chitomur®) Blood Vessels (Ventfort®) Bone Marrow (Bonomarlot®) Cartilage (Sigumir®) CNS/ Brain (Cerluten®) Heart (Chelohart®)

(Nature’s Marvels™) Kidney (Pielotax®) Liver (Svetinorm®) Lungs (Taxorest®) Muscle (Gotratix®) Ovaries (Zhenoluten®) Pancreas (Suprefort®) Parathyroid (Bonothyrk®)

Pineal (Endoluten®) Prostate (Libidon®) Retina (Visoluten®) Stomach (Stamakort®) Testes (Testoluten®) Thymus (Vladonix®) Thyroid (Thyreogen®)

SMARTS Adrafinil (AdraPro™) Centrophenoxine (CentroPro™) Deprenyl (DepPro™)

Hydergine® (HyPro™) Idebenone Modafinil (ModaPro™)

Picamilone (PicPro™) Piracetam (PiraPro™) Reminyl® (Galantamine)

SPECIALIST (INCLUDING MEDICINES) 4MU (4MUPro™) Acarbose (Glucobay®) Aminoguanidine (AminoPro™) Anastrozole (Arimidex®) B17-Pro™ (amadaylin) Bromocriptine (Parlodel®) Cabergoline (Dostinex®)

BEC5® Curaderm cream Can-C™ eye-drops Joint-Pro™ cream Oraltide™ repair gel

Hydrocortisone (HydrocortPro™) Melatonin (MZS™) MSH2 (MSH2Pro™) Oxytocin (OxyPro™)

Pregnenolone (PregPro™) Progesterone (ProgestPro™) Thyroids (Armour™, T3, etc.) TRH (Abaris™) Vasopressin (VasoPro™)

Dasatinib (Dasa-Pro™) DMSA (DMSAPro™) Doxycycline Dutasteride (Avodart®) EDTA (EDTA-Pro2™) Finasteride (Proscar®)

GH3Pro™ (Gerovital-H3®) Metformin (MetPro™) Naltrexone (NalPro™) Rapamycin (RapaPro™) Sildenafil (SildenafilPro™) Tadalafil (TadalafilPro™)

Oraltide™ mouthwash Youth Gems®

Disclaimer: All educational information is provided under the IAS terms and conditions which may change without notice. Restrictions may apply in some countries. (*plus S&H).

Can-C eye-drops 2 x 5ml vials

NUTRITION 1st Line™ (OSCN) Benfotiamine (Milgamma™) Boluoke® (Lumbrokinase) Beta-Glucans (BG-Pro™) Boost-Pro™

TA65® capsules (250) GCB70-Pro™ NAD+ (NAD+Pro™)

TOPICALS

HORMONES Aldosterone (AldoPro™) Desmopressin (Minurin®) DHEA (DHEAPro™) Estrogens(Esnatri™) HCG (HCGPro™)

Vitamin D3 (D3-5000™) MultiV45-Pro™ PEA (Pain-Pro™) TA65® capsules (100)

ACF-228® Boluoke® (Lumbrokinase) Can-C™ + capsules Carnosine (Carno-Pro™) DIM (DIM-Pro3™)

L-tryptophan (Ltryp-Pro™) NADH Novisyn® (Hyaluronan) PQQ (PQQ-Pro™) Symprove®

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